Donald Malone

Cleveland Clinic, Cleveland, Ohio, United States

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Publications (31)

  • Murat Altinay · Emad Estemalik · Donald A. Malone
    [Show abstract] [Hide abstract] ABSTRACT: Background Neurostimulation as a treatment option for refractory neuropsychiatric disorders has been increasingly utilized in recent years. For patients with such refractory disorders who have often failed to respond to various medical interventions, deep brain stimulation (DBS) has emerged as a promising treatment modality. DBS is a reversible and adjustable form of brain stimulation (also known as functional neurosurgery) in which desired brain structures (or circuits) are given focal electric stimulation via electrodes that are implanted in the brain tissue during a surgical procedure. It has been utilized among various psychiatric and neurological illnesses, in particular headache disorders.This article reviews the most relevant data regarding DBS for psychiatric and primary headache disorders.Methods Authors conducted a detailed literature search of Medline/PubMed database and studies that used DBS for the treatment of refractory neuropsychiatric disorders were reviewed. Response, remission, and safety measures of these studies were obtained.ResultsDespite the advancement in DBS treatment, the number of randomized controlled studies remains very limited due to ethical and methodological difficulties of setting up invasive procedures of this magnitude. So at present, DBS represents a modality used only in the most refractory patients.Conclusion Current data support DBS as a promising treatment option for neuropsychiatric disorders that do not respond to conventional treatments; however, it is clear that more research and patient volume is needed to demonstrate its efficacy in treating these conditions. The use of functional imaging to understand the pathophysiology of these disorders has been crucial for the utilization of DBS.
    Article · Mar 2015 · Headache The Journal of Head and Face Pain
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    Darin D Dougherty · Ali R Rezai · Linda L Carpenter · [...] · Donald A Malone
    [Show abstract] [Hide abstract] ABSTRACT: Multiple open-label trials of deep brain stimulation (DBS) for treatment-resistant depression (TRD), including those targeting the ventral capsule/ventral striatum target, have shown encouraging response rates. However, no randomized controlled trials of DBS for TRD have been published. Thirty patients with TRD participated in a sham-controlled trial of DBS at the ventral capsule/ventral striatum target for TRD. Patients were randomized to active versus sham DBS treatment in a blinded fashion for 16 weeks, followed by an open-label continuation phase. The primary outcome measure was response, defined as a 50% or greater improvement on the Montgomery-Åsberg Depression Rating Scale from baseline. There was no significant difference in response rates between the active (3 of 15 subjects; 20%) and control (2 of 14 subjects; 14.3%) treatment arms and no significant difference between change in Montgomery-Åsberg Depression Rating Scale scores as a continuous measure upon completion of the 16-week controlled phase of the trial. The response rates at 12, 18, and 24 months during the open-label continuation phase were 20%, 26.7%, and 23.3%, respectively. The results of this first randomized controlled study of DBS for the treatment of TRD did not demonstrate a significant difference in response rates between the active and control groups at the end of the 16-week controlled phase. However, a range of 20% to 26.7% of patients did achieve response at any time during the open-label continuation phase. Future studies, perhaps utilizing alternative study designs and stimulation parameters, are needed. Copyright © 2014 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
    Full-text Article · Dec 2014 · Biological Psychiatry
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    Michael L Kelly · Donald Malone · Michael S Okun · [...] · Andre G Machado
    [Show abstract] [Hide abstract] ABSTRACT: The success of device-based research in the clinical neurosciences has overshadowed a critical and emerging problem in the biomedical research environment in the United States. Neuroprosthetic devices, such as deep brain stimulation (DBS), have been shown in humans to be promising technologies for scientific exploration of neural pathways and as powerful treatments. Large device companies have, over the past several decades, funded and developed major research programs. However, both the structure of clinical trial funding and the current regulation of device research threaten investigator-initiated efforts in neurologic disorders. The current atmosphere dissuades clinical investigators from pursuing formal and prospective research with novel devices or novel indications. We review our experience in conducting a federally funded, investigator-initiated, device-based clinical trial that utilized DBS for thalamic pain syndrome. We also explore barriers that clinical investigators face in conducting device-based clinical trials, particularly in early-stage studies or small disease populations. We discuss 5 specific areas for potential reform and integration: (1) alternative pathways for device approval; (2) eliminating right of reference requirements; (3) combining federal grant awards with regulatory approval; (4) consolidation of oversight for human subjects research; and (5) private insurance coverage for clinical trials. Careful reformulation of regulatory policy and funding mechanisms is critical for expanding investigator-initiated device research, which has great potential to benefit science, industry, and, most importantly, patients.
    Full-text Article · Mar 2014 · Neurology
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    Cynthia S Kubu · Donald A Malone · Gordon Chelune · [...] · Benjamin D Greenberg
    [Show abstract] [Hide abstract] ABSTRACT: Background: Deep brain stimulation (DBS) has shown promise as a treatment for severe, highly treatment-refractory obsessive-compulsive disorder (OCD) or major depressive disorder (MDD). We describe the neuropsychological outcome in 21 patients (10 OCD and 11 MDD) who received DBS in the anterior limb of the internal capsule/ventral striatum (VC/VS). Methods: All patients completed a preoperative and postoperative neuropsychological battery. Average duration of DBS stimulation was 8.91 months (SD = 4.63) at the time of follow-up testing. Data were analyzed using practice-effect-corrected change scores. Results: No significant cognitive declines were seen. There were significant improvements in prose passage recall after chronic DBS. The cognitive improvements were not related to change in severity of OCD, depression or global impairment. Conclusions: This preliminary study suggests that VC/VS DBS does not result in cognitive declines. The observations that verbal memory improved are consistent with current theories on the role of the VS in the memory, but require replication in larger studies.
    Full-text Article · Oct 2013 · Stereotactic and Functional Neurosurgery
  • Elizabeth Shultz · Donald A Malone
    [Show abstract] [Hide abstract] ABSTRACT: Although antidepressant drugs do not differ much in their efficacy rates, the particular characteristics of one drug may make it a better choice in a given patient. This article provides insight into the art of prescribing antidepressants in primary care, with recommendations for prescribing for patients with chronic pain, sexual dysfunction, anxiety, chronic fatigue syndrome, fibromyalgia, severe insomnia, old age, diabetes, and heart problems.
    Article · Oct 2013 · Cleveland Clinic Journal of Medicine
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    Ela B Plow · Donald A Malone · Andre Machado
    [Show abstract] [Hide abstract] ABSTRACT: Chronic neuropathic pain in thalamic pain syndrome remains intractable. Its poor response is ascribed to destruction of the integrated neuromatrix in experience of pain. Deep brain stimulation is a promising technique to modulate activity of implicated structures. However, traditional approaches targeting sensori-motor substrates have failed to affect disability. The offending lesion in thalamic pain syndrome that almost invariably destroys sensory pain pathways may render these classical approaches ineffective. Instead, we hypothesize that targeting structures representing emotion and affective behavior-ventral striatum/anterior limb of the internal capsule, may alleviate disability.Methods/design: We present the design of our phase I randomized, double-blinded, sham-controlled, crossover trial that examines safety, feasibility and efficacy of our proposed approach. In our ongoing trial, we intend to enroll ten patients with thalamic pain syndrome. Following implantation, patients are randomized to receive active deep brain stimulation to the ventral striatum/anterior limb of the internal capsule or sham for 3 months, after which they are crossed over. The primary endpoint is Pain Disability Index. Other outcomes include visual analog scale, depression and anxiety inventories, quality of life, and functional neuroimaging. Designing trials of deep brain stimulation for pain is challenging owing to the ethical-scientific dilemma of introducing a control arm, complicated blinding, heterogeneous etiologies, patient expectations, and inadequate assessment of disability. The quality of evidence in the field is classified as level III (poor) because it mainly includes a multitude of uncontrolled case series reporting variable outcomes, with little regard for the placebo effect related to implantation. Without valid data on efficacy, use of deep brain stimulation for pain remains "off label". We present our trial design to discuss feasibility of conducting sham-controlled phase I studies that may represent significant refinement for the field. Double-blinding would reduce influence of patient expectations and therapeutic confusion amongst investigators. With a cross-over approach, the dilemma regarding including a control group can be mitigated. Use of homogeneous etiology, measurement of disability, depression and quality of life, besides pain perception, all represent strategies to evaluate efficacy rigorously. Functional imaging would serve to define mechanisms underlying observed effects and may help optimize future targeting.Trial registration: NCT01072656.
    Full-text Article · Jul 2013 · Trials
  • Alexander S Taghva · Donald A Malone · Ali R Rezai
    [Show abstract] [Hide abstract] ABSTRACT: Background: Major depressive disorder is a common and disabling illness and is the leading cause of disability worldwide. Despite aggressive medical, behavioral, and electroconvulsive therapies, a significant number of patients remain refractory to treatment. Deep brain stimulation (DBS) has proven efficacy in neurobehavioral disorders and, in a general sense, works by modulation of corticostriatopallidothalamocortical circuits implicated in these disorders. Methods: Current data, treatment rationales, and future directions are presented. Results: The two targets most commonly used for DBS in treatment-resistant depression are the subgenual cingulate gyrus and the ventral capsule/ventral striatum. Data on DBS of these regions are preliminary, with promise shown in early studies. Conclusions: Early work suggests DBS may become a therapeutic option in treatment-resistant depression. Further study is justified given the immense burden of disease.
    Article · Oct 2012 · World Neurosurgery
  • Andre G Machado · Kenneth B Baker · Ela Plow · Donald A Malone
    [Show abstract] [Hide abstract] ABSTRACT: Objectives: To review the current state of cerebral stimulation for neuropathic pain and to propose that cerebral stimulation should aim also at the affective sphere of chronic pain rather than solely focusing on the primary sensory-discriminative sphere. Methods: The past and current goals of cerebral stimulation are reviewed as well as its limitations. A novel deep brain stimulation approach is proposed to evaluate this conceptual shift from somatosensory to affective sphere of pain targeting. Approach: Thalamic and other central pain syndromes are typically intractable to current treatment methods, including cerebral neuromodulation of somatosensory pathways, leading to long-term distress and disability. Our modern understanding of chronic pain pathophysiology is based largely on the neuromatrix theory, where cognitive, affective, and sensory-discriminative spheres contribute equally to the overall pain experience. During the last decade, the safety and feasibility of chronic stimulation of neural pathways related to mood and affect has been explored with promising results. Here, we propose a novel approach to modulate the affective sphere of chronic pain by targeting similar networks in patients with treatment-refractory central pain. Our primary goal is not to produce (or measure) analgesia, but rather to modulate the affective burden of chronic pain. Discussion: Cerebral neuromodulation for neuropathic pain has had limited efficacy thus far. Shifting our aim to neural networks related to the affective sphere of pain may allow us to reduce pain conditioning and pain-related disability. Our ultimate goal is to promote rehabilitation from chronic pain-social and occupational.
    Article · Oct 2012 · Neuromodulation
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    Mayur Pandya · Murat Altinay · Donald A Malone · Amit Anand
    [Show abstract] [Hide abstract] ABSTRACT: Major depressive disorder is a serious medical illness which is responsible for considerable morbidity and disability. Despite decades of research, the neural basis for depression is still incompletely understood. In this review, evidence from neuroimaging, neuropsychiatric and brain stimulations studies are explored to answer the question regarding the localization of depression in the brain. Neuroimaging studies indicate that although many regions of the brain have been repeatedly implicated in the pathophysiology of depression, not many consistent findings have been found until present. In recent times, the focus of neuroimaging has shifted from regional brain abnormalities to circuit level connectivity abnormalities. However, connectivity models are inherently more complicated, and the validity of these models remains to be tested. Neuropsychiatric studies of illnesses such as Parkinson's disease and stroke provide promising clues regarding areas involved in depression, but again consistent findings are rare. Similarly, stimulation of a variety of brain regions and circuits has been reported as being effective in depression. Therefore, the current knowledge indicates that the pathophysiology of depression may be distributed across many brain regions and circuits. In future studies, this distributed nature of depression needs to be further investigated, primary and secondary areas affected need to be identified, and new paradigms to explain complex mental functions need to be explored.
    Full-text Article · Oct 2012 · Current Psychiatry Reports
  • J Luis Lujan · Ashutosh Chaturvedi · Donald A Malone · [...] · Cameron C McIntyre
    [Show abstract] [Hide abstract] ABSTRACT: The underlying hypothesis of our work is that specific clinical neuropsychiatric benefits can be achieved by selective activation of specific axonal pathways during deep brain stimulation (DBS). As such, the goal of this study was to develop a method for identifying axonal pathways whose activation is most likely necessary for achieving therapeutic benefits during DBS. Our approach combined clinical data, diffusion tensor tractography, and computer models of patient-specific neurostimulation to identify particular axonal pathways activated by DBS and determine their correlations with individual clinical outcome measures. We used this method to evaluate a cohort of seven treatment-resistant depression patients treated with DBS of the ventral anterior internal capsule and ventral striatum (VC/VS). Clinical responders exhibited five axonal pathways that were consistently activated by DBS. All five pathways coursed lateral and medial to the VS or dorsal and lateral to the nucleus accumbens; however, details of their specific trajectories differed. Similarly, one common pathway was identified across nonresponders. Our method and preliminary results provide important background for studies aiming to expand scientific characterization of neural circuitry associated with specific psychiatric outcomes from DBS. Furthermore, identification of pathways linked to therapeutic benefit provides opportunities to improve clinical selection of surgical targets and stimulation settings for DBS devices.
    Article · Apr 2012 · Human Brain Mapping
  • Mayur Pandya · Andre Machado · Donald Malone
    [Show abstract] [Hide abstract] ABSTRACT: The use of deep brain stimulation (DBS) of the ventral capsule/ventral striatum (VC/VS) for the treatment of major depressive disorder (MDD) stems from pioneering work in obsessive–compulsive disorder. Understanding the rationale for the VC/VS target chosen for investigation of MDD requires an appreciation of the neuroanatomical structures and their positioning relative to each other. Presently, there are no consensus guidelines or algorithms for DBS patient selection, surgical implantation, or programming in depression. DBS of the VC/VS for the treatment of depression remains investigational and not approved by the Food and Drug Administration. With our experience over the past decade in 16 patients who underwent DBS electrode implantation at the VC/VS for the treatment of depression at our clinic, we have been able to delineate trends and common responses that may assist in the programming of this population. The development of this emerging therapy depends on advances in neurosurgical technique and patient selection, as well as furthering our understanding of the circuitry involved in the targeted region.
    Chapter · Jan 2012
  • Andre Machado · Donald Malone
    Article · Nov 2011 · Neurosurgery
  • Article · Oct 2010 · Psychiatric Annals
  • [Show abstract] [Hide abstract] ABSTRACT: To assess the behavioral and subjective effects of acute electrical stimulation along the anterior limb of the internal capsule (ALIC) and ventral striatum (VS). Intraoperative awake electrical stimulation and postoperative programming was performed in a group of 6 patients with major depressive disorder (MDD) undergoing bilateral deep brain stimulation of the ALIC and VS areas. Electrical stimulation of the VS area acutely produced changes in mood as well as alertness, anxiety, dizziness, sensation of warmth and "flushing". Stimulation of the ventral capsule area just dorsal to the anterior commissure was associated with increments in mood, sensation of energy and alertness, laughing, calmness and talkative behavior. Behavioral effects were less commonly observed with stimulation of the dorsal region of the ALIC. Acute behavioral and subjective responses can be consistently obtained from stimulation in the ventral ALIC and VS region. Positive changes in mood and anxiety were reproducibly elicited in the ventral ALIC area. Intraoperative awake stimulation and postoperative programming of patients undergoing DBS for MDD provide unique opportunities to explore the subjective responses and behavioral phenomena related to electrical stimulation of the area spanning from the dorsal ALIC to the ventral striatum.
    Article · Sep 2009 · Clinical neurophysiology: official journal of the International Federation of Clinical Neurophysiology
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    Donald A Malone · Darin D Dougherty · Ali R Rezai · [...] · Benjamin D Greenberg
    [Show abstract] [Hide abstract] ABSTRACT: We investigated the use of deep brain stimulation (DBS) of the ventral capsule/ventral striatum (VC/VS) for treatment refractory depression. Fifteen patients with chronic, severe, highly refractory depression received open-label DBS at three collaborating clinical sites. Electrodes were implanted bilaterally in the VC/VS region. Stimulation was titrated to therapeutic benefit and the absence of adverse effects. All patients received continuous stimulation and were followed for a minimum of 6 months to longer than 4 years. Outcome measures included the Hamilton Depression Rating Scale-24 item (HDRS), the Montgomery-Asberg Depression Rating Scale (MADRS), and the Global Assessment of Function Scale (GAF). Significant improvements in depressive symptoms were observed during DBS treatment. Mean HDRS scores declined from 33.1 at baseline to 17.5 at 6 months and 14.3 at last follow-up. Similar improvements were seen with the MADRS (34.8, 17.9, and 15.7, respectively) and the GAF (43.4, 55.5, and 61.8, respectively). Responder rates with the HDRS were 40% at 6 months and 53.3% at last follow-up (MADRS: 46.7% and 53.3%, respectively). Remission rates were 20% at 6 months and 40% at last follow-up with the HDRS (MADRS: 26.6% and 33.3%, respectively). The DBS was well-tolerated in this group. Deep brain stimulation of the VC/VS offers promise for the treatment of refractory major depression.
    Full-text Article · Nov 2008 · Biological psychiatry
  • [Show abstract] [Hide abstract] ABSTRACT: Over the past 20 years, there has been a concerted effort to expand our understanding of the neural circuitry involved in the pathogenesis of psychiatric disorders. Distinct neuronal circuits and networks have been implicated in obsessive compulsive disorder (OCD) and major depressive disorder (MDD) involving feedback loops between the cortex, striatum, and thalamus. When neurosurgery is used as a therapeutic tool in severe OCD and MDD, the goal is to modulate specific targets or nodes within these networks in an effort to produce symptom relief.Currently, four lesioning neurosurgical procedures are utilized for treatment refractory OCD and MDD: cingulotomy, capsulotomy, subcaudate tractotomy, and limbic leucotomy. Deep brain stimulation (DBS) is a novel neurosurgical approach that has some distinct advantages over lesioning procedures. With DBS, the desired clinical effect can be achieved by reversible, high frequency stimulation in a nucleus or at a node in the circuit without the need to produce an irreversible lesion. Recent trials of deep brain stimulation in both OCD and MDD at several neuroanatomical targets have reported promising early results in highly refractory patients and with a good safety profile. Future definitive trials in MDD and OCD are envisaged.
    Article · Oct 2008 · Psychiatry
  • Article · Jun 2008 · Neurosurgery
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    Full-text Conference Paper · Apr 2008
  • Ali R. Rezai · Donald Malone · Darin Dougherty · [...] · Steven Rasmussen
    Conference Paper · Apr 2008
  • Kenneth B Baker · Brian H Kopell · Donald Malone · [...] · Ali R Rezai
    [Show abstract] [Hide abstract] ABSTRACT: To demonstrate the pattern of activation associated with electrical stimulation through bilateral deep brain stimulation electrodes placed within the anterior limb of the internal capsule to the level of the ventral striatum for treatment of obsessive-compulsive disorder. A 44-year-old man with a 26-year history of obsessive-compulsive disorder underwent functional magnetic resonance imaging (fMRI) and deep brain stimulation-evoked cortical potential testing after bilateral implantation of deep brain stimulation leads. Stimulation was delivered independently through the distal two contacts of each percutaneously extended lead using an external pulse generator. On postoperative Day 2, we used a 3-Tesla magnetic resonance system to measure changes in the fMRI blood oxygen level-dependent signal using stimulation parameters that were predetermined to demonstrate behavioral effects. All studies were well tolerated. Trial stimulations performed intraoperatively as well as on postsurgical Day 1 were associated with acutely elevated mood and reduced anxiety. Although the benefit achieved acutely was relatively symmetric between the bilaterally placed leads, follow-up programming showed a clear advantage to right-sided stimulation. Three of the four fMRI trials demonstrated good activation, with the fourth being moderately corrupted by motion artifact. The beneficial effects observed with right-sided stimulation were associated with activation of the ipsilateral head of the caudate, medial thalamus, and anterior cingulate cortex as well as the contralateral cerebellum. The distribution of the cortical evoked potentials was consistent with the locus of cortical activation observed with fMRI. High-frequency stimulation via a lead placed in the anterior limb of the internal capsule induced widespread hemodynamic changes at both the cortical and subcortical levels including areas typically associated with the pathogenesis of obsessive-compulsive disorder.
    Article · Dec 2007 · Neurosurgery

Publication Stats

2k Citations


  • 2014
    • Cleveland Clinic
      • Department of Psychiatry and Psychology
      Cleveland, Ohio, United States
  • 2010
    • Brown University
      Providence, Rhode Island, United States
  • 2006
    • Massachusetts General Hospital
      • Department of Psychiatry
      Boston, Massachusetts, United States