Baron Short

A Feasibility Study of a New Method for Electrically Producing Seizures in Man: Focal Electrically Administered Seizure Therapy (FEAST)

BACKGROUND Electroconvulsive therapy (ECT) remains the most effective acute treatment for severe major depression, but with significant risk of adverse cognitive effects. Unidirectional electrical stimulation with a novel electrode placement and geometry (Focal Electrically Administered Seizure Therapy (FEAST)) has been proposed as a means to initiate seizures in prefrontal cortex prior to secondary generalization. As such, it may have fewer cognitive side effects than traditional ECT. We report on its first human clinical application. METHOD Seventeen unmedicated depressed adults (5 men; 3 bipolar disorder; age 53 ± 16 years) were recruited after being referred for ECT. Open-label FEAST was administered with a modified spECTrum 5000Q device and a traditional ECT dosing regimen until patients clinically responded. Clinical and cognitive assessments were obtained at baseline, and end of course. Time to orientation recovery, a predictor of long-term amnestic effects, was assessed at each treatment. Nonresponders to FEAST were transitioned to conventional ECT. RESULTS One patient withdrew from the study after a single titration session. After the course of FEAST (median 10 sessions), there was a 46.1 ± 35.5% improvement in Hamilton Rating Scale for Depression (HRSD24) scores compared to baseline (33.1 ± 6.8, 16.8 ± 10.9; P < 0.0001). Eight of 16 patients met response criteria (50% decrease in HRSD24) and 5/16 met remission criteria (HRSD24 ≤ 10). Patients achieved full re-orientation (4 of 5 items) in 5.5 ± 6.4 min (median = 3.6), timed from when their eyes first opened after treatment. CONCLUSION In this feasibility study, FEAST produced clinically meaningful antidepressant improvement, with relatively short time to reorientation. Our preliminary work first in primates and now depressed adults demonstrates that FEAST is feasible, safe, well-tolerated and, if efficacy can be optimized, has potential to replace traditional ECT.

Regional cerebral blood flow changes associated with focal electrically administered seizure therapy (FEAST).

INTRODUCTION Use of electroconvulsive therapy (ECT) is limited by cognitive disturbance. Focal electrically-administered seizure therapy (FEAST) is designed to initiate focal seizures in the prefrontal cortex. To date, no studies have documented the effects of FEAST on regional cerebral blood flow (rCBF). METHODS A 72 year old depressed man underwent three single photon emission computed tomography (SPECT) scans to capture the onset and resolution of seizures triggered with right unilateral FEAST. We used Bioimage Suite for within-subject statistical analyses of perfusion differences ictally and post-ictally compared with the baseline scan. RESULTS Early ictal increases in regional cerebral blood flow (rCBF) were limited to the right prefrontal cortex. Post-ictally, perfusion was reduced in bilateral frontal and occipital cortices and increased in left motor and precuneus cortex. CONCLUSION FEAST appears to triggers focal onsets of seizure activity in the right prefrontal cortex with subsequent generalization. Future studies are needed on a larger sample.

Treating the depressions with superficial brain stimulation methods.

Many, if not most, of the different superficial brain stimulation methods are being either used or investigated to treat the depressions. There are likely many reasons why there is this much interest and research involving brain stimulation treatments for depression, including that the depressions are common, there is dissatisfaction with other treatments, and some patients do not respond to medications or talking therapies. This is coupled with the fact that depressive episodes are a periodic or temporary state of the brain, and that when patients are no longer in that state they return to normal functioning. Additionally, the oldest brain stimulation method, electroconvulsive therapy (ECT), is also the most effective antidepressant available for the acute treatment of depression in patients who do not respond to medications. The newer brain stimulation methods have followed in the path blazed by ECT, showing that stimulation of key regions can cause a change in brain state and treat the depression. After almost 20 years of research, repeated daily repetitive transcranial magnetic stimulation (rTMS) of the prefrontal cortex for several weeks is now also an established clinical treatment for acute episodes. The data are less convincing for the other brain stimulation methods, but all are being investigated. Using brain stimulation (as opposed to medications or talking therapy) to treat depression is a rapidly expanding area of research with already established clear indications. Much more work is needed to understand best which methods should be used in any given patient, and in what order.

A Double-Blind Study Exploring the Use of Transcranial Direct Current Stimulation (tDCS) to Potentially Enhance Mindfulness Meditation (E-Meditation)

Please cite this article as: Bashar W. Badran, Chris W. Austelle, Nicole R. Smith, Chloe E. Glusman, Brett Froeliger, Eric L Garland, Jeffrey J. Borckardt, Mark S. George, Baron Short, A Double-Blind Study Exploring the Use of Transcranial Direct Current Stimulation (tDCS) to Potentially Enhance Mindfulness Meditation (E-Meditation), Brain Stimulation (2016), http://dx.doi.org/doi: 10.1016/j.brs.2016.09.009.

Safe management of a bipolar depressed patient with prefrontal repetitive transcranial magnetic stimulation (rTMS) Over 7 years and >2 million stimuli.

team.” The title of the paper of Zibetti et al. reads: “Does intraoperative microelectrode recording really increase the risk of hemorrhagic complications in deep brain stimulation?” This title contains one superfluous word but it also lacks other important words. The superfluous word is “intraoperative.” I am not aware of any preoperative or postoperative MER; MER is always intraoperative. On the other hand, the words lacking from the title are more important: the title should have been “Does microelectrode recording in Turin really increase the risk of hemorrhagic complications in deep brain stimulation?” Clearly, at the San Giovanni Battista Hospital in Turin, MER does not increase the risk of hemorrhagic complications in DBS. For this, the authors are certainly to be congratulated. However, based on the wealth of available literature, the answer to the general question remains a resounding YES. Yes, indeed MER does increase the risk of hemorrhagic complications in DBS. MER is not a homogeneous technique: some centers like Zibetti et al. almost always use one single MER track while others systematically use five tracks (on each brain hemisphere); yet others use as many as they deem necessary to “map” the target area. Given the lack of head to head comparison in a randomized manner of DBS surgery using any MER technique versus DBS surgery not using MER, the next best is a meta-analysis of the available literature, as has been performed by Zrinzo et al. recently [2]. In that study, it was demonstrated without the shadow of doubt that the use of MER and the number of MER tracks do impact negatively on the risk of hemorrhage, all other factors such as high age, hypertension etc. being equal. Adding data from the 221 Turin patients to the thousands of patients included in this meta-analysis does not alter these findings. Clearly, the routine passage of multiple sharp probes through the brain is likely to increase the risk of hemorrhage. Therefore, it would be tedious to list all the studies and reports about the additional risk of hemorrhage with MER in functional stereotactic neurosurgery. Suffice to quote a couple of studies: In 2001, Alkhani and Lozano analysed 85 articles about pallidotomy from 40 centers in 12 countries, with 1959 operated patients; MER was performed in 46.2% of the patients and no MER in 53.8%. Cerebral hemorrhage occurred in 2.7% of MER procedures and in 0.5% of non-MER procedures [3]. In 2009, the Harvard group reported 3.8% symptomatic hemorrhage in 130 patients undergoing MER-guided DBS [4]. Nine years earlier, the same group had reported on 75 patients who underwent pallidotomy (i.e. ablative surgery!) without MER, and without a single symptomatic hemorrhage [5]. MER is without doubt an exquisite tool for research and it is a pity that most group who use some kind of MER do not profit from this unique tool to learn more about the neuronal properties of the various brain target areas during DBS procedures, and disseminate their acquired knowledge. In conclusion, the paper of Zibetti et al. confirms the excellent safety of MER-guided DBS performed at San Giovanni Battista Hospital in Turin. However, it does not affect the overwhelming body of evidence that MER is associated with an increased risk of hemorrhage during functional neurosurgical procedures.

Increased Prolactin Concentrations in a Patient with Bipolar Disorder

A 58-year-old woman in the depressive phase of bipolar disorder ( BPD)3 type 1 enrolled in a clinical study of the efficacy of a new form of electroconvulsive therapy (ECT) for her depression, because ECT has not been commonly used for the treatment for BPD or depression. BPD is any of several mood disorders characterized by alternating episodes of depression and mania or by episodes of depression alternating with mild nonpsychotic excitement. BPD type 1 is distinguished from type 2 according to the severity of increased mood symptoms (1). At study enrollment, the patient reported severe sadness, a lack of motivation, fatigue, general malaise, feelings of guilt, and an increased need for sleep, but she had no suicidal or homicidal thoughts. She had no history of galactorrhea. A physical examination revealed nothing outstanding except decreased tendon reflexes in the patellar and the achilles, and a small nodule on the closure site from a previous hysterectomy. A cranial computed axial tomography (CAT) scan was performed to assess for increased intracranial pressure before proceeding with ECT; no unusual findings were noted. Initial blood tests showed a serum sodium concentration of 135 mEq/L (135 mmol/L; reference interval, 135–145 mmol/L), a high triglyceride concentration [217 mg/dL (2.45 mmol/L); reference interval, <150 mg/dL (<1.69 mmol/L)], and a VLDL cholesterol concentration of 43 mg/dL [1.11 mmol/L; reference interval, <30 mg/dL (<0.78 mmol/L)]. The results of a urine drug screen for amphetamines, barbiturates, benzodiazepine, cannabinoids, cocaine, opiates, and phencyclidine were negative. As per the study protocol, a baseline blood sample was drawn 5 min before treatment, and at 5, 15, 30, 45 min after seizure termination. Prolactin (PRL) concentrations were assessed from these blood draws during the second and fourth treatments of the study by means of a 2-site sandwich immunochemiluminometric assay (Siemens ADVIA Centaur® System). These …

Neuroversion: using electroconvulsive therapy as a bridge to deep brain stimulation implantation

ABSTRACT Parkinson’s disease (PD) is a movement disorder with significant neuropsychiatric comorbidities. Electroconvulsive therapy (ECT) is effective in treating these neuropsychiatric symptoms; however, clinicians are reluctant to use ECT in patients with deep brain stimulation (DBS) implantations for fear of damaging the device, as well as potential cognitive side effects. Right unilateral ultra-brief pulse (RUL UBP) ECT has a more favorable cognitive side-effect profile yet has never been reported in PD patients with DBS implants. We present a case series of three patients with a history of PD that all presented with psychiatric decompensation immediately prior to planned DBS surgery. All three patients had DBS electrode(s) in place at the time and an acute course of ECT was utilized in a novel method to “bridge” these individuals to neurosurgery. The patients all experienced symptom resolution (psychosis and/or depression and/or anxiety) without apparent cognitive side effects. This case series not only illustrates that right unilateral ultra-brief pulse can be utilized in patients with DBS electrodes but also illustrates that this intervention can be utilized as a neuromodulatory “bridge”, where nonoperative surgical candidates with unstable psychiatric symptoms can be converted to operative candidates in a manner similar to electrical cardioversion.

EP 23. Bilateral epidural prefrontal cortical stimulation (EpCS) over fronto-polar and mid-frontal gyrus accesses mood regulation networks: Evidence from diffusion tensor imaging

Introduction The functional neuroanatomy of depression involves the prefrontal, cingulate and insular cortices, the amygdala, the nucleus accumbens and the hippocampus. The anterior and lateral prefrontal cortices are different in their cognitive and emotional integration roles and their modulation of sub-cortical regions. Both offer a distinct opportunity for targeted antidepressant treatments. Epidural prefrontal cortical stimulation (EpCS) is a unique therapeutic approach. It is more direct than transcranial magnetic stimulation (TMS) or vagus nerve stimulation (VNS), safer than deep brain stimulation (DBS) and, when applied chronically can reduce negative emotional arousal, increases stress tolerance and possibly lead to fewer relapses than observed with antidepressant pharmacotherapy Question Document the direct anatomical connections accessed with bilateral EpCS over fronto-polar and mid-frontal gyrus using diffusion tensor imaging (DTI). Methods Five patients treatment-resistant depression were implanted with bilateral EpCS leads over fronto-polar and mid-frontal gyrus. Patients underwent structural imaging (high resolution T1-weighted (T1w) MRI image and a DTI with 32 gradient directions) before surgery and a CT scan post-implantation. Image analysis was performed using the FMRIB Software Library. BA25, BA10 and BA46 areas, and Amygdala were extracted from the Broadmann area template to serve as guides for tractography. Similarly, individual EpCS paddles identified on CT scan were also transformed. First, an affine (12 parameter model) registration was applied to register Broadmann template onto T1w images and then T1w onto DTI data. Transformations were then applied to the guides. Second, a binary mask of the brain was extracted and applied to all images after correction for eddy currents. BedpostX was then run on the preprocessed data to generate the basis for probabilistic tractography using ProbtrackX. Estimation of tracts was done probabilistically, using a dual-fiber model with 5000 tract-following samples at each voxel. All tractography was done in each subject’s native space. Eight tractography combinations (left & right) were performed: BA10/BA46 as seeds for tractography and Amygdala/BA25 as waypoints masks. Similar approached was applied with EpCS actual lead masks. The resulting fibers were then thresholded at 0.01 (99% likelihood of connectivity) and then binarized, and transferred into MNI152 standard space for cross-subject analysis using a non-linear registration. To generate population-based probability fibers, all subjects’ individual fibers were added up and used as a basis for calculation of a mean image. Finally, the resulting mean fiber was thresholded to show voxels common to 80% or more of the subjects. Results All patients showed robust connections of different pathways in both left and right hemispheres. The resulting pathways connected to each seed combination are shown in Fig. 1 . Electrodes implanted over both BA10 and BA46 areas resulted in direct activation of axons that primarily project from BA10 or BA46 to BA25 and Amygdala, and extend to the cingulum bundle and to the middle occipital gyrus. Conclusion This is the first demonstration of EpCS direct anatomical access to the medial and lateral mood regulation networks. Encouraging clinical data have been reported elsewhere with 3 patients out of 5 showing remission at 7 months (Nahas et al., 2010) and at 5 years (Williams et al., under review). Bilateral anterior and lateral EpCS promises to be an innovative new treatment for a highly morbid disease through adaptive cortical governance of limbic structures but larger studies are needed.