Nolan Williams

All Publications

• Targeted neurostimulation reverses a spatiotemporal biomarker of treatment-resistant depression. Proceedings of the National Academy of Sciences of the United States of America Mitra, A., Raichle, M. E., Geoly, A. D., Kratter, I. H., Williams, N. R. 2023; 120 (21): e2218958120

  Abstract

  Major depressive disorder (MDD) is widely hypothesized to result from disordered communication across brain-wide networks. Yet, prior resting-state-functional MRI (rs-fMRI) studies of MDD have studied zero-lag temporal synchrony (functional connectivity) in brain activity absent directional information. We utilize the recent discovery of stereotyped brain-wide directed signaling patterns in humans to investigate the relationship between directed rs-fMRI activity, MDD, and treatment response to FDA-approved neurostimulation paradigm termed Stanford neuromodulation therapy (SNT). We find that SNT over the left dorsolateral prefrontal cortex (DLPFC) induces directed signaling shifts in the left DLPFC and bilateral anterior cingulate cortex (ACC). Directional signaling shifts in the ACC, but not the DLPFC, predict improvement in depression symptoms, and moreover, pretreatment ACC signaling predicts both depression severity and the likelihood of SNT treatment response. Taken together, our findings suggest that ACC-based directed signaling patterns in rs-fMRI are a potential biomarker of MDD.

  View details for DOI 10.1073/pnas.2218958120

  View details for PubMedID 37186863

• Stanford Neuromodulation Therapy (SNT): A Double-Blind Randomized Controlled Trial. The American journal of psychiatry Cole, E. J., Phillips, A. L., Bentzley, B. S., Stimpson, K. H., Nejad, R., Barmak, F., Veerapal, C., Khan, N., Cherian, K., Felber, E., Brown, R., Choi, E., King, S., Pankow, H., Bishop, J. H., Azeez, A., Coetzee, J., Rapier, R., Odenwald, N., Carreon, D., Hawkins, J., Chang, M., Keller, J., Raj, K., DeBattista, C., Jo, B., Espil, F. M., Schatzberg, A. F., Sudheimer, K. D., Williams, N. R. 2021: appiajp202120101429

  Abstract

  OBJECTIVE: Depression is the leading cause of disability worldwide, and half of patients with depression have treatment-resistant depression. Intermittent theta-burst stimulation (iTBS) is approved by the U.S. Food and Drug Administration for the treatment of treatment-resistant depression but is limited by suboptimal efficacy and a 6-week duration. The authors addressed these limitations by developing a neuroscience-informed accelerated iTBS protocol, Stanford neuromodulation therapy (SNT; previously referred to as Stanford accelerated intelligent neuromodulation therapy, or SAINT). This protocol was associated with a remission rate of 90% after 5 days of open-label treatment. Here, the authors report the results of a sham-controlled double-blind trial of SNT for treatment-resistant depression.METHODS: Participants with treatment-resistant depression currently experiencing moderate to severe depressive episodes were randomly assigned to receive active or sham SNT. Resting-state functional MRI was used to individually target the region of the left dorsolateral prefrontal cortex most functionally anticorrelated with the subgenual anterior cingulate cortex. The primary outcome was score on the Montgomery-Asberg Depression Rating Scale (MADRS) 4 weeks after treatment.RESULTS: At the planned interim analysis, 32 participants with treatment-resistant depression had been enrolled, and 29 participants who continued to meet inclusion criteria received either active (N=14) or sham (N=15) SNT. The mean percent reduction from baseline in MADRS score 4 weeks after treatment was 52.5% in the active treatment group and 11.1% in the sham treatment group.CONCLUSIONS: SNT, a high-dose iTBS protocol with functional-connectivity-guided targeting, was more effective than sham stimulation for treatment-resistant depression. Further trials are needed to determine SNT's durability and to compare it with other treatments.

  View details for DOI 10.1176/appi.ajp.2021.20101429

  View details for PubMedID 34711062

• Stanford Accelerated Intelligent Neuromodulation Therapy for Treatment-Resistant Depression. The American journal of psychiatry Cole, E. J., Stimpson, K. H., Bentzley, B. S., Gulser, M. n., Cherian, K. n., Tischler, C. n., Nejad, R. n., Pankow, H. n., Choi, E. n., Aaron, H. n., Espil, F. M., Pannu, J. n., Xiao, X. n., Duvio, D. n., Solvason, H. B., Hawkins, J. n., Guerra, A. n., Jo, B. n., Raj, K. S., Phillips, A. L., Barmak, F. n., Bishop, J. H., Coetzee, J. P., DeBattista, C. n., Keller, J. n., Schatzberg, A. F., Sudheimer, K. D., Williams, N. R. 2020: appiajp201919070720

  Abstract

  New antidepressant treatments are needed that are effective, rapid acting, safe, and tolerable. Intermittent theta-burst stimulation (iTBS) is a noninvasive brain stimulation treatment that has been approved by the U.S. Food and Drug Administration for treatment-resistant depression. Recent methodological advances suggest that the current iTBS protocol might be improved through 1) treating patients with multiple sessions per day at optimally spaced intervals, 2) applying a higher overall pulse dose of stimulation, and 3) precision targeting of the left dorsolateral prefrontal cortex (DLPFC) to subgenual anterior cingulate cortex (sgACC) circuit. The authors examined the feasibility, tolerability, and preliminary efficacy of Stanford Accelerated Intelligent Neuromodulation Therapy (SAINT), an accelerated, high-dose resting-state functional connectivity MRI (fcMRI)-guided iTBS protocol for treatment-resistant depression.Twenty-two participants with treatment-resistant depression received open-label SAINT. fcMRI was used to individually target the region of the left DLPFC most anticorrelated with sgACC in each participant. Fifty iTBS sessions (1,800 pulses per session, 50-minute intersession interval) were delivered as 10 daily sessions over 5 consecutive days at 90% resting motor threshold (adjusted for cortical depth). Neuropsychological testing was conducted before and after SAINT.One participant withdrew, leaving a sample size of 21. Nineteen of 21 participants (90.5%) met remission criteria (defined as a score <11 on the Montgomery-Åsberg Depression Rating Scale). In the intent-to-treat analysis, 19 of 22 participants (86.4%) met remission criteria. Neuropsychological testing demonstrated no negative cognitive side effects.SAINT, an accelerated, high-dose, iTBS protocol with fcMRI-guided targeting, was well tolerated and safe. Double-blinded sham-controlled trials are needed to confirm the remission rate observed in this initial study.

  View details for DOI 10.1176/appi.ajp.2019.19070720

  View details for PubMedID 32252538

• Attenuation of antidepressant and antisuicidal effects of ketamine by opioid receptor antagonism. Molecular psychiatry Williams, N. R., Heifets, B. D., Bentzley, B. S., Blasey, C. n., Sudheimer, K. D., Hawkins, J. n., Lyons, D. M., Schatzberg, A. F. 2019

  Abstract

  We recently reported that naltrexone blocks antidepressant effects of ketamine in humans, indicating that antidepressant effects of ketamine require opioid receptor activation. However, it is unknown if opioid receptors are also involved in ketamine's antisuicidality effects. Here, in a secondary analysis of our recent clinical trial, we test whether naltrexone attenuates antisuicidality effects of ketamine. Participants were pretreated with naltrexone or placebo prior to intravenous ketamine in a double-blinded crossover design. Suicidality was measured with the Hamilton Depression Rating Scale item 3, Montgomery-Åsberg Depression Rating Scale item 10, and Columbia Suicide Severity Rating Scale. In the 12 participants who completed naltrexone and placebo conditions, naltrexone attenuated the antisuicidality effects of ketamine on all three suicidality scales/subscales (linear mixed model, fixed pretreatment effect, p < 0.01). Results indicate that opioid receptor activation plays a significant role in the antisuicidality effects of ketamine.

  View details for DOI 10.1038/s41380-019-0503-4

  View details for PubMedID 31467392

• Attenuation of Antidepressant Effects of Ketamine by Opioid Receptor Antagonism. The American journal of psychiatry Williams, N. R., Heifets, B. D., Blasey, C., Sudheimer, K., Pannu, J., Pankow, H., Hawkins, J., Birnbaum, J., Lyons, D. M., Rodriguez, C. I., Schatzberg, A. F. 2018: appiajp201818020138

  Abstract

  OBJECTIVE: In addition to N-methyl-d-aspartate receptor antagonism, ketamine produces opioid system activation. The objective of this study was to determine whether opioid receptor antagonism prior to administration of intravenous ketamine attenuates its acute antidepressant or dissociative effects.METHOD: In a proposed double-blind crossover study of 30 adults with treatment-resistant depression, the authors performed a planned interim analysis after studying 14 participants, 12 of whom completed both conditions in randomized order: placebo or 50 mg of naltrexone preceding intravenous infusion of 0.5 mg/kg of ketamine. Response was defined as a reduction ≥50% in score on the 17-item Hamilton Depression Rating Scale (HAM-D) score on postinfusion day 1.RESULTS: In the interim analysis, seven of 12 adults with treatment-resistant depression met the response criterion during the ketamine plus placebo condition. Reductions in 6-item and 17-item HAM-D scores among participants in the ketamine plus naltrexone condition were significantly lower than those of participants in the ketamine plus placebo condition on postinfusion days 1 and 3. Secondary analysis of all participants who completed the placebo and naltrexone conditions, regardless of the robustness of response to ketamine, showed similar results. There were no differences in ketamine-induced dissociation between conditions. Because naltrexone dramatically blocked the antidepressant but not the dissociative effects of ketamine, the trial was halted at the interim analysis.CONCLUSIONS: The findings suggest that ketamine's acute antidepressant effect requires opioid system activation. The dissociative effects of ketamine are not mediated by the opioid system, and they do not appear sufficient without the opioid effect to produce the acute antidepressant effects of ketamine in adults with treatment-resistant depression.

  View details for PubMedID 30153752

• High-dose spaced theta-burst TMS as a rapid-acting antidepressant in highly refractory depression. Brain : a journal of neurology Williams, N. R., Sudheimer, K. D., Bentzley, B. S., Pannu, J. n., Stimpson, K. H., Duvio, D. n., Cherian, K. n., Hawkins, J. n., Scherrer, K. H., Vyssoki, B. n., DeSouza, D. n., Raj, K. S., Keller, J. n., Schatzberg, A. F. 2018

  View details for PubMedID 29415152

• Five Year Follow-Up of Bilateral Epidural Prefrontal Cortical Stimulation for Treatment-Resistant Depression BRAIN STIMULATION Williams, N. R., Short, E. B., Hopkins, T., Bentzle, B. S., Sahlem, G. L., Pannu, J., Schmidt, M., Borckardt, J. J., Korte, J. E., George, M. S., Takacs, I., Nahas, Z. 2016; 9 (6): 897-904

  Abstract

  Epidural prefrontal cortical stimulation (EpCS) represents a novel therapeutic approach with many unique benefits that can be used for treatment-resistant depression (TRD).To examine the long-term safety and efficacy of EpCS of the frontopolar cortex (FPC) and dorsolateral prefrontal cortex (DLPFC) for treatment of TRD.Adults (N = 5) who were 21-80 years old with severe TRD [failure to respond to adequate courses of at least 4 antidepressant medications, psychotherapy and ≥20 on the Hamilton Rating Scale for Depression (HRSD24)] were recruited. Participants were implanted with bilateral EpCS over the FPC and DLPFC and received constant, chronic stimulation throughout the five years with Medtronic IPGs. They were followed for 5 years (2/1/2008-10/14/2013). Efficacy of EpCS was assessed with the HRSD24 in an open-label design as the primary outcome measure at five years.All 5 patients continued to tolerate the therapy. The mean improvements from pre-implant baseline on the HRSD24 were [7 months] 54.9% (±37.7), [1 year] 41.2% (±36.6), [2 years] 53.8% (±21.7), and [5 years] 45% (±47). Three of 5 (60%) subjects continued to be in remission at 5 years. There were 5 serious adverse events: 1 electrode 'paddle' infection and 4 device malfunctions, all resulting in suicidal ideation and/or hospitalization.These results suggest that chronic bilateral EpCS over the FPC and DLPFC is a promising and potentially durable new technology for treating TRD, both acutely and over 5 years.

  View details for DOI 10.1016/j.brs.2016.06.054

  View details for Web of Science ID 000387197500013

  View details for PubMedID 27443912

• Deep brain stimulation (DBS) at the interface of neurology and psychiatry JOURNAL OF CLINICAL INVESTIGATION Williams, N. R., Okun, M. S. 2013; 123 (11): 4546-4556

  Abstract

  Deep brain stimulation (DBS) is an emerging interventional therapy for well-screened patients with specific treatment-resistant neuropsychiatric diseases. Some neuropsychiatric conditions, such as Parkinson disease, have available and reasonable guideline and efficacy data, while other conditions, such as major depressive disorder and Tourette syndrome, have more limited, but promising results. This review summarizes both the efficacy and the neuroanatomical targets for DBS in four common neuropsychiatric conditions: Parkinson disease, Tourette syndrome, major depressive disorder, and obsessive-compulsive disorder. Based on emerging new research, we summarize novel approaches to optimization of stimulation for each neuropsychiatric disease and we review the potential positive and negative effects that may be observed following DBS. Finally, we summarize the likely future innovations in the field of electrical neural-network modulation.

  View details for DOI 10.1172/JCI68341

  View details for Web of Science ID 000326611900002

  View details for PubMedID 24177464

  View details for PubMedCentralID PMC3809784

• Treatment-resistant depression: definition, prevalence, detection, management, and investigational interventions. World psychiatry : official journal of the World Psychiatric Association (WPA) McIntyre, R. S., Alsuwaidan, M., Baune, B. T., Berk, M., Demyttenaere, K., Goldberg, J. F., Gorwood, P., Ho, R., Kasper, S., Kennedy, S. H., Ly-Uson, J., Mansur, R. B., McAllister-Williams, R. H., Murrough, J. W., Nemeroff, C. B., Nierenberg, A. A., Rosenblat, J. D., Sanacora, G., Schatzberg, A. F., Shelton, R., Stahl, S. M., Trivedi, M. H., Vieta, E., Vinberg, M., Williams, N., Young, A. H., Maj, M. 2023; 22 (3): 394-412

  Abstract

  Treatment-resistant depression (TRD) is common and associated with multiple serious public health implications. A consensus definition of TRD with demonstrated predictive utility in terms of clinical decision-making and health outcomes does not currently exist. Instead, a plethora of definitions have been proposed, which vary significantly in their conceptual framework. The absence of a consensus definition hampers precise estimates of the prevalence of TRD, and also belies efforts to identify risk factors, prevention opportunities, and effective interventions. In addition, it results in heterogeneity in clinical practice decision-making, adversely affecting quality of care. The US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have adopted the most used definition of TRD (i.e., inadequate response to a minimum of two antidepressants despite adequacy of the treatment trial and adherence to treatment). It is currently estimated that at least 30% of persons with depression meet this definition. A significant percentage of persons with TRD are actually pseudo-resistant (e.g., due to inadequacy of treatment trials or non-adherence to treatment). Although multiple sociodemographic, clinical, treatment and contextual factors are known to negatively moderate response in persons with depression, very few factors are regarded as predictive of non-response across multiple modalities of treatment. Intravenous ketamine and intranasal esketamine (co-administered with an antidepressant) are established as efficacious in the management of TRD. Some second-generation antipsychotics (e.g., aripiprazole, brexpiprazole, cariprazine, quetiapine XR) are proven effective as adjunctive treatments to antidepressants in partial responders, but only the olanzapine-fluoxetine combination has been studied in FDA-defined TRD. Repetitive transcranial magnetic stimulation (TMS) is established as effective and FDA-approved for individuals with TRD, with accelerated theta-burst TMS also recently showing efficacy. Electroconvulsive therapy is regarded as an effective acute and maintenance intervention in TRD, with preliminary evidence suggesting non-inferiority to acute intravenous ketamine. Evidence for extending antidepressant trial, medication switching and combining antidepressants is mixed. Manual-based psychotherapies are not established as efficacious on their own in TRD, but offer significant symptomatic relief when added to conventional antidepressants. Digital therapeutics are under study and represent a potential future clinical vista in this population.

  View details for DOI 10.1002/wps.21120

  View details for PubMedID 37713549

  View details for PubMedCentralID PMC10503923

• Network effects of Stanford Neuromodulation Therapy (SNT) in treatment-resistant major depressive disorder: a randomized, controlled trial. Translational psychiatry Batail, J., Xiao, X., Azeez, A., Tischler, C., Kratter, I. H., Bishop, J. H., Saggar, M., Williams, N. R. 2023; 13 (1): 240

  Abstract

  Here, we investigated the brain functional connectivity (FC) changes following a novel accelerated theta burst stimulation protocol known as Stanford Neuromodulation Therapy (SNT) which demonstrated significant antidepressant efficacy in treatment-resistant depression (TRD). In a sample of 24 patients (12 active and 12 sham), active stimulation was associated with significant pre- and post-treatment modulation of three FC pairs, involving the default mode network (DMN), amygdala, salience network (SN) and striatum. The most robust finding was the SNT effect on amygdala-DMN FC (group*time interaction F(1,22)=14.89, p<0.001). This FC change correlated with improvement in depressive symptoms (rho (Spearman) = -0.45, df=22, p=0.026). The post-treatment FC pattern showed a change in the direction of the healthy control group and was sustained at the one-month follow-up. These results are consistent with amygdala-DMN connectivity dysfunction as an underlying mechanism of TRD and bring us closer to the goal of developing imaging biomarkers for TMS treatment optimization.Trial registration: ClinicalTrials.gov NCT03068715.

  View details for DOI 10.1038/s41398-023-02537-9

  View details for PubMedID 37400432

• No place in France for repetitive transcranial magnetic stimulation in the therapeutic armamentarium of treatment-resistant depression? Brain stimulation Batail, J. M., Gaillard, R., Haffen, E., Poulet, E., Sauvaget, A., Szekely, D., Brunelin, J., Bulteau, S., Bubrovszky, M., Smadja, J., Bourla, A., Bouaziz, N., Januel, D., Rotharmel, M., Arns, M., Downar, J., Fitzgerald, P. B., Brunoni, A. R., Pallanti, S., D'Urso, G., Baeken, C., Williams, N. R., Millet, B., Lefaucheur, J. P., Drapier, D. 2023

  View details for DOI 10.1016/j.brs.2023.05.015

  View details for PubMedID 37245843

• Accelerated Repetitive Transcranial Magnetic Stimulation to Treat Major Depression: The Past, Present, and Future. Harvard review of psychiatry Chen, L., Klooster, D. C., Tik, M., Thomas, E. H., Downar, J., Fitzgerald, P. B., Williams, N. R., Baeken, C. 2023; 31 (3): 142-161

  Abstract

  Repetitive transcranial magnetic stimulation (rTMS) is an effective and evidence-based therapy for treatment-resistant major depressive disorder. A conventional course of rTMS applies 20-30 daily sessions over 4-6 weeks. The schedule of rTMS delivery can be accelerated by applying multiple stimulation sessions per day, which reduces the duration of a treatment course with a predefined number of sessions. Accelerated rTMS reduces time demands, improves clinical efficiency, and potentially induces faster onset of antidepressant effects. However, considerable heterogeneity exists across study designs. Stimulation protocols vary in parameters such as the stimulation target, frequency, intensity, number of pulses applied per session or over a course of treatment, and duration of intersession intervals. In this article, clinician-researchers and neuroscientists who have extensive research experience in accelerated rTMS synthesize a consensus based on two decades of investigation and development, from early studies ("Past") to contemporaneous theta burst stimulation, a time-efficient form of rTMS gaining acceptance in clinical settings ("Present"). We propose descriptive nomenclature for accelerated rTMS, recommend avenues to optimize therapeutic and efficiency potential, and suggest using neuroimaging and electrophysiological biomarkers to individualize treatment protocols ("Future"). Overall, empirical studies show that accelerated rTMS protocols are well tolerated and not associated with serious adverse effects. Importantly, the antidepressant efficacy of accelerated rTMS appears comparable to conventional, once daily rTMS protocols. Whether accelerated rTMS induces antidepressant effects more quickly remains uncertain. On present evidence, treatment protocols incorporating high pulse dose and multiple treatments per day show promise and improved efficacy.

  View details for DOI 10.1097/HRP.0000000000000364

  View details for PubMedID 37171474

• Repetitive Transcranial Magnetic Stimulation for Treatment-Resistant Depression: Mismatch of Evidence and Insurance Coverage Policies in the United States. The Journal of clinical psychiatry Weissman, C. R., Bermudes, R. A., Voigt, J., Liston, C., Williams, N., Blumberger, D. M., Fitzgerald, P. B., Daskalakis, Z. J. 2023; 84 (3)

  View details for DOI 10.4088/JCP.22com14575

  View details for PubMedID 37103918

• Real-Time Semi-Automated and Automated Voxel Placement using fMRI Targets for Repeated Acquisition Magnetic Resonance Spectroscopy. Journal of neuroscience methods Bishop, J. H., Geoly, A., Khan, N., Tischler, C., Krueger, R., Keshava, P., Amin, H., Baltusis, L., Wu, H., Spiegel, D., Williams, N., Sacchet, M. D. 2023: 109853

  Abstract

  BACKGROUND: Currently, magnetic resonance spectroscopy (MRS) is dependent on the investigative team to manually prescribe, or demarcate, the desired tissue volume-of-interest. The need for a new method to automate precise voxel placements is warranted to improve the utility and interpretability of MRS data.NEW METHOD: We propose and validate robust and real-time methods to automate MRS voxel placement using functionally defined coordinates within the prefrontal cortex. Data were collected and analyzed using two independent prospective studies: 1) two independent imaging days with each consisting of a multi-session sandwich design (MRS data only collected on one of the days determined based on scan time) and 2) a longitudinal design. Participants with fibromyalgia syndrome (N=50) and major depressive disorder (N=35) underwent neuroimaging. MRS acquisitions were acquired at 3-tesla. Evaluation of the reproducibility of spatial location and tissue segmentation was assessed for: 1) manual, 2) semi-automated, and 3) automated voxel prescription approaches RESULTS: Variability of voxel grey and white matter tissue composition was reduced using automated placement protocols. Spatially, post- to pre-voxel center-of-gravity distance was reduced and voxel overlap increased significantly across datasets using automated compared to manual procedures COMPARISON WITH EXISTING METHODS: Manual prescription, the current standard in the field, can produce inconsistent data across repeated acquisitions. Using automated voxel placement, we found reduced variability and more consistent voxel placement across multiple acquisitions CONCLUSIONS: These results demonstrate the within subject reliability and reproducibility of a method for reducing variability introduced by spatial inconsistencies during MRS acquisitions. The proposed method is a meaningful advance toward improved consistency of MRS data in neuroscience and can be utilized for multi-session and longitudinal studies.

  View details for DOI 10.1016/j.jneumeth.2023.109853

  View details for PubMedID 37031764

• Time for Brain Medicine. The Journal of neuropsychiatry and clinical neurosciences Brown, J. C., Dainton-Howard, H., Woodward, J., Palmer, C., Karamchandani, M., Williams, N. R., George, M. S. 2023: appineuropsych21120312

  Abstract

  Unprecedented knowledge of the brain is inevitably contributing to the convergence of neurology and psychiatry. However, clinical training continues to follow a divergent approach established in the 19th century. An etiological approach will continue to shift more psychiatric patients to the care of neurologists who are untrained in psychiatric management. At the same time, this new era of diagnostic biomarkers and neuroscience-based precision treatments requires skills not readily available to those trained in psychiatry. The challenges in training the next generation of doctors include establishing competence involving aspects of the whole brain, fostering the subspecialized expertise needed to remain current, and developing programs that are feasible in duration and practical in implementation. A new 4-year residency training program proposed in this article could replace existing residency programs. The program includes 2 years of common and urgent training in various aspects of neurology and psychiatry followed by 2 years of elective subspecialty tracks. The concept is similar to internal medicine residencies and fellowships. No changes to existing departmental structures are necessary. In concert with the emerging biological approach to the brain, "brain medicine" is proposed as a new name to denote this practice in the simplest terms: a focus on all aspects of the brain.

  View details for DOI 10.1176/appi.neuropsych.21120312

  View details for PubMedID 37021384

• Taking modern psychiatry into the metaverse: Integrating augmented, virtual, and mixed reality technologies into psychiatric care. Frontiers in digital health Ford, T. J., Buchanan, D. M., Azeez, A., Benrimoh, D. A., Kaloiani, I., Bandeira, I. D., Hunegnaw, S., Lan, L., Gholmieh, M., Buch, V., Williams, N. R. 2023; 5: 1146806

  Abstract

  The landscape of psychiatry is ever evolving and has recently begun to be influenced more heavily by new technologies. One novel technology which may have particular application to psychiatry is the metaverse, a three-dimensional digital social platform accessed via augmented, virtual, and mixed reality (AR/VR/MR). The metaverse allows the interaction of users in a virtual world which can be measured and manipulated, posing at once exciting new possibilities and significant potential challenges and risks. While the final form of the nascent metaverse is not yet clear, the immersive simulation and holographic mixed reality-based worlds made possible by the metaverse have the potential to redefine neuropsychiatric care for both patients and their providers. While a number of applications for this technology can be envisioned, this article will focus on leveraging the metaverse in three specific domains: medical education, brain stimulation, and biofeedback. Within medical education, the metaverse could allow for more precise feedback to students performing patient interviews as well as the ability to more easily disseminate highly specialized technical skills, such as those used in advanced neurostimulation paradigms. Examples of potential applications in brain stimulation and biofeedback range from using AR to improve precision targeting of non-invasive neuromodulation modalities to more innovative practices, such as using physiological and behavioral measures derived from interactions in VR environments to directly inform and personalize treatment parameters for patients. Along with promising future applications, we also discuss ethical implications and data security concerns that arise when considering the introduction of the metaverse and related AR/VR technologies to psychiatric research and care.

  View details for DOI 10.3389/fdgth.2023.1146806

  View details for PubMedID 37035477

  View details for PubMedCentralID PMC10080019

• Appetitive Mapping of the Human Nucleus Accumbens. Biological psychiatry Parker, J. J., Rolle, C. E., Shivacharan, R. S., Barbosa, D. A., Feng, A., Huang, Y., Kakusa, B. W., Prieto, T., Jaffe, R. A., Williams, N. R., Halpern, C. H. 2022

  View details for DOI 10.1016/j.biopsych.2022.09.016

  View details for PubMedID 36509559

• Aberrant impulse control circuitry in obesity. Molecular psychiatry Barbosa, D. A., Kuijper, F. M., Duda, J., Wang, A. R., Cartmell, S. C., Saluja, S., Cunningham, T., Shivacharan, R. S., Bhati, M. T., Safer, D. L., Lock, J. D., Malenka, R. C., de Oliveira-Souza, R., Williams, N. R., Grossman, M., Gee, J. C., McNab, J. A., Bohon, C., Halpern, C. H. 2022

  Abstract

  The ventromedial prefrontal cortex (vmPFC) to nucleus accumbens (NAc) circuit has been implicated in impulsive reward-seeking. This disinhibition has been implicated in obesity and often manifests as binge eating, which is associated with worse treatment outcomes and comorbidities. It remains unclear whether the vmPFC-NAc circuit is perturbed in impulsive eaters with obesity. Initially, we analyzed publicly available, high-resolution, normative imaging data to localize where vmPFC structural connections converged within the NAc. These structural connections were found to converge ventromedially in the presumed NAc shell subregion. We then analyzed multimodal clinical and imaging data to test the a priori hypothesis that the vmPFC-NAc shell circuit is linked to obesity in a sample of female participants that regularly engaged in impulsive eating (i.e., binge eating). Functionally, vmPFC-NAc shell resting-state connectivity was inversely related to body mass index (BMI) and decreased in the obese state. Structurally, vmPFC-NAc shell structural connectivity and vmPFC thickness were inversely correlated with BMI; obese binge-prone participants exhibited decreased vmPFC-NAc structural connectivity and vmPFC thickness. Finally, to examine a causal link to binge eating, we directly probed this circuit in one binge-prone obese female using NAc deep brain stimulation in a first-in-human trial. Direct stimulation of the NAc shell subregion guided by local behaviorally relevant electrophysiology was associated with a decrease in number of weekly episodes of uncontrolled eating and decreased BMI. This study unraveled vmPFC-NAc shell circuit aberrations in obesity that can be modulated to restore control over eating behavior in obesity.

  View details for DOI 10.1038/s41380-022-01640-5

  View details for PubMedID 35697760

• Hypnotic predictors of agency: Responsiveness to specific suggestions in hypnosis is associated with involuntariness in fibromyalgia. Consciousness and cognition Faerman, A., Stimpson, K. H., Bishop, J. H., Neri, E., Phillips, A., Gulser, M., Amin, H., Nejad, R., Fotros, A., Williams, N. R., Spiegel, D. 2021; 96: 103221

  Abstract

  Hypnosis is associated with alterations in the sense of agency which can play a role in its utilization as a nonpharmacological option for pain management. The goal of the current study was to examine the relationships between responsiveness to suggestions in hypnosis and alterations of the sense of agency among patients with fibromyalgia. Ninety-eight participants with fibromyalgia underwent two hypnotizability assessments followed by the Sense of Agency Rating Scale. Clinical pain measures were also collected. Involuntariness was predicted by responsiveness to control, ideomotor, and dissociation suggestions. Effortlessness was predicted by responsiveness to control and ideomotor suggestions, and age. Hypnotizability was associated with main clinical pain outcomes, but agency alterations were not. Results suggest a shared mechanism between responsiveness to specific suggestions and the sense of agency in hypnosis. We discuss theoretical and clinical implications for pain management and the need for further research.

  View details for DOI 10.1016/j.concog.2021.103221

  View details for PubMedID 34695719

• Unraveling the opioid actions of S-ketamine and R-ketamine: comment on Bonaventura et al. Molecular psychiatry Heifets, B. D., Bentzley, B. S., Williams, N., Schatzberg, A. F. 2021

  View details for DOI 10.1038/s41380-021-01167-1

  View details for PubMedID 34006965

• Accelerated Neuromodulation Therapy for Obsessive-Compulsive Disorder. Brain stimulation Williams, N. R., Sudheimer, K. D., Cole, E. J., Varias, A. D., Goldstein-Piekarski, A. N., Stetz, P. n., Lombardi, A. n., Filippou-Frye, M. n., van Roessel, P. n., Anderson, K. n., McCarthy, E. A., Wright, B. n., Sandhu, T. n., Menon, S. n., Jo, B. n., Koran, L. n., Williams, L. M., Rodriguez, C. I. 2021

  Abstract

  The open-label trial of Williams, Sudheimer, Cole, et al., suggests safety, feasibility, and high efficacy for treatment-refractory OCD of an accelerated, fMRI-guided, high-dose, cTBSmod protocol targeting the right frontal pole. Larger, randomized, controlled trials are needed to test the promising results of this pilot study. CLINICALTRIALS.GOV REGISTRY NUMBERS: NCT03404609.

  View details for DOI 10.1016/j.brs.2021.02.013

  View details for PubMedID 33631349

• The Future of Training and Practice in Neuromodulation: An Interventional Psychiatry Perspective. Frontiers in psychiatry Trapp, N. T., Williams, N. R. 2021; 12: 734487

  View details for DOI 10.3389/fpsyt.2021.734487

  View details for PubMedID 34512426

• Lather, Rinse, Repeat? Breaking Repetitive Behaviors With Repetitive Stimulation. The American journal of psychiatry Lissemore, J. I., Williams, N. R. 2021; 178 (5): 378–80

  View details for DOI 10.1176/appi.ajp.2020.21030265

  View details for PubMedID 33979540

• Synchronized Cervical VNS With Accelerated Theta Burst TMS For Treatment Resistant Depression. Brain stimulation George, M. S., Caulfield, K. A., O'Leary, K., Badran, B. W., Short, E. B., Huffman, S. M., Li, X., Kerns, S. E., Williams, N. R. 2020

  View details for DOI 10.1016/j.brs.2020.08.002

  View details for PubMedID 32777436

• Transcranial Magnetic Stimulation Parameter Space: Wide Open for Exploration. Biological psychiatry Bentzley, B. S., Williams, N. R. 2020; 87 (5): 384–85

  View details for DOI 10.1016/j.biopsych.2019.11.012

  View details for PubMedID 32029073

• Evidence for the role of the dorsal ventral lateral posterior thalamic nucleus connectivity in deep brain stimulation for Gilles de la Tourette syndrome. Journal of psychiatric research Kakusa, B. n., Saluja, S. n., Barbosa, D. A., Cartmell, S. n., Espil, F. M., Williams, N. R., McNab, J. A., Halpern, C. H. 2020; 132: 60–64

  Abstract

  Gilles de la Tourette syndrome (GTS) can manifest as debilitating, medically-refractory tics for which deep brain stimulation (DBS) of the centromedian-parafascicular complex (CM) can provide effective treatment. However, patients have reported benefit with activation of contacts dorsal to the CM and likely in the ventro-lateral thalamus (VL). At our institution, a case of a robust and durable response in a GTS patient required stimulation in the CM and more dorsally. We explore the structural connectivity of thalamic subregions associated with GTS using diffusion MRI tractography. Diffusion weighted images from 40 healthy Human Connectome Project (HCP) subjects and our GTS patient were analyzed. The VL posterior nucleus (VLp) and the CM were used as seeds for whole-brain probabilistic tractography. Leads were localized via linear registration of pre-/post-operative imaging and cross-referenced with the DBS Intrinsic Template Atlas. Tractography revealed high streamline probability from the CM and VLp to the superior frontal gyrus, rostral middle frontal gyrus, brainstem, and ventral diencephalon. Given reported variable responses to DBS along the thalamus, we segmented the VLp based on its connectivity profile. Ventral and dorsal subdivisions emerged, with streamline probability patterns differing between the dorsal VLp and CM. The CM, the most reported DBS target for GTS, and the dorsal VLp have different but seemingly complimentary connectivity profiles as evidenced by our patient who, at 1-year post-operatively, had significant therapeutic benefit. Stimulation of both regions may better target reward and motor circuits, resulting in enhanced symptom control for GTS.

  View details for DOI 10.1016/j.jpsychires.2020.09.024

  View details for PubMedID 33045620

• Brain-Responsive Neurostimulation for Loss of Control Eating: Early Feasibility Study. Neurosurgery Wu, H. n., Adler, S. n., Azagury, D. E., Bohon, C. n., Safer, D. L., Barbosa, D. A., Bhati, M. T., Williams, N. R., Dunn, L. B., Tass, P. A., Knutson, B. D., Yutsis, M. n., Fraser, A. n., Cunningham, T. n., Richardson, K. n., Skarpaas, T. L., Tcheng, T. K., Morrell, M. J., Roberts, L. W., Malenka, R. C., Lock, J. D., Halpern, C. H. 2020

  Abstract

  Loss of control (LOC) is a pervasive feature of binge eating, which contributes significantly to the growing epidemic of obesity; approximately 80 million US adults are obese. Brain-responsive neurostimulation guided by the delta band was previously found to block binge-eating behavior in mice. Following novel preclinical work and a human case study demonstrating an association between the delta band and reward anticipation, the US Food and Drug Administration approved an Investigational Device Exemption for a first-in-human study.To assess feasibility, safety, and nonfutility of brain-responsive neurostimulation for LOC eating in treatment-refractory obesity.This is a single-site, early feasibility study with a randomized, single-blinded, staggered-onset design. Six subjects will undergo bilateral brain-responsive neurostimulation of the nucleus accumbens for LOC eating using the RNS® System (NeuroPace Inc). Eligible participants must have treatment-refractory obesity with body mass index ≥ 45 kg/m2. Electrophysiological signals of LOC will be characterized using real-time recording capabilities coupled with synchronized video monitoring. Effects on other eating disorder pathology, mood, neuropsychological profile, metabolic syndrome, and nutrition will also be assessed.Safety/feasibility of brain-responsive neurostimulation of the nucleus accumbens will be examined. The primary success criterion is a decrease of ≥1 LOC eating episode/week based on a 28-d average in ≥50% of subjects after 6 mo of responsive neurostimulation.This study is the first to use brain-responsive neurostimulation for obesity; this approach represents a paradigm shift for intractable mental health disorders.

  View details for DOI 10.1093/neuros/nyaa300

  View details for PubMedID 32717033

• Deep Brain Stimulation Results in Greater Symptomatic Improvement in Tourette Syndrome than Conservative Measures: A Meta-Analysis. Stereotactic and functional neurosurgery Mahajan, U. V., Purger, D. A., Mantovani, A. n., Williams, N. R., Epsil, F. M., Han, S. S., Stein, S. C., Halpern, C. H. 2020: 1–8

  Abstract

  Deep brain stimulation (DBS) has emerged as a safe and effective therapy for refractory Tourette syndrome (TS). Recent studies have identified several neural targets as effective in reducing TS symptoms with DBS, but, to our knowledge, none has compared the effectiveness of DBS with conservative therapy.A literature review was performed to identify studies investigating adult patient outcomes reported as Yale Global Tic Severity Scale (YGTSS) scores after DBS surgery, pharmacotherapy, and psychotherapy. Data were pooled using a random-effects model of inverse variance-weighted meta-analysis (n = 168 for DBS, n = 131 for medications, and n = 154 for behavioral therapy).DBS resulted in a significantly greater reduction in YGTSS total score (49.9 ± 17.5%) than pharmacotherapy (22.5 ± 15.2%, p = 0.001) or psychotherapy (20.0 ± 11.3%, p < 0.001), with a complication (adverse effect) rate of 0.15/case, 1.13/case, and 0.60/case, respectively.Our data suggest that adult patients with refractory TS undergoing DBS experience greater symptomatic improvement with surprisingly low morbidity than can be obtained with pharmacotherapy or psychotherapy.

  View details for DOI 10.1159/000507059

  View details for PubMedID 32434201

• Multimodal characterization of the human nucleus accumbens NEUROIMAGE Cartmell, S. D., Tian, Q., Thio, B. J., Leuze, C., Ye, L., Williams, N. R., Yang, G., Ben-Dor, G., Deisseroth, K., Grill, W. M., McNab, J. A., Halpern, C. H. 2019; 198: 137–49

  View details for DOI 10.1016/j.neuroimage.2019.05.019

  View details for Web of Science ID 000472495100013

• Rigorous Trial Design Is Essential to Understand the Role of Opioid Receptors in Ketamine's Antidepressant Effect JAMA PSYCHIATRY Heifets, B. D., Williams, N. R., Bentzley, B. S., Schatzberg, A. F. 2019; 76 (6): 657–58

  View details for DOI 10.1001/jamapsychiatry.2019.0766

  View details for Web of Science ID 000474836500016

• Attenuation of Anti-Suicidal Effects of Ketamine by Opioid Receptor Antagonism Williams, N., Heifets, B., Bentzley, B., Blasey, C., Sudheimer, K., Lyons, D., Schatzberg, A. ELSEVIER SCIENCE INC. 2019: S113

  View details for DOI 10.1016/j.biopsych.2019.03.284

  View details for Web of Science ID 000472661000271

• Stanford Accelerated Intelligent Neuromodulation Therapy for Suicidal Ideation (SAINT-SI) Williams, N. ELSEVIER SCIENCE INC. 2019: S28

  View details for DOI 10.1016/j.biopsych.2019.03.081

  View details for Web of Science ID 000472661000068

• The Effects of Cortisol Administration on Emotion, Stress Reactivity, and Brain Activity in Depression Sudheimer, K., Duvio, D., James, D., Heinemeyer, E., Pirog, S., Williams, N., Schatzberg, A. ELSEVIER SCIENCE INC. 2019: S267

  View details for DOI 10.1016/j.biopsych.2019.03.677

  View details for Web of Science ID 000472661000652

• Rigorous Translational Models Are Key to Studying Ketamine's Antidepressant Mechanism: Response to Wang and Kaplin. The American journal of psychiatry Heifets, B. D., Williams, N. R., Blasey, C., Sudheimer, K., Rodriguez, C. I., Schatzberg, A. F. 2019; 176 (5): 412

  View details for PubMedID 31039633

• Robust clinical benefit of multi-target deep brain stimulation for treatment of Gilles de la Tourette syndrome and its comorbidities BRAIN STIMULATION Kakusa, B., Saluja, S., Tate, W. J., Espil, F. M., Halpern, C. H., Williams, N. R. 2019; 12 (3): 816–18

  View details for DOI 10.1016/j.brs.2019.02.026

  View details for Web of Science ID 000465395800038

• Rigorous Translational Models Are Key to Studying Ketamine's Antidepressant Mechanism: Response to Wang and Kaplin AMERICAN JOURNAL OF PSYCHIATRY Heifets, B. D., Williams, N. R., Blasey, C., Sudheimer, K., Rodriguez, C. I., Schatzberg, A. F. 2019; 176 (5): 412

  View details for DOI 10.1176/appi.ajp.2019.19010044r

  View details for Web of Science ID 000466364500015

• Rigorous Trial Design Is Essential to Understand the Role of Opioid Receptors in Ketamine's Antidepressant Effect. JAMA psychiatry Heifets, B. D., Williams, N. R., Bentzley, B. S., Schatzberg, A. F. 2019

  View details for PubMedID 31042274

• Case Studies in Neuroscience: The electrophysiology of a human obsession in nucleus accumbens. Journal of neurophysiology Miller, K. J., Prieto, T., Williams, N. R., Halpern, C. H. 2019

  Abstract

  Microelectrode recordings were performed during awake deep brain stimulation surgery for obsessive-compulsive disorder, revealing robust brain oscillations that were plainly visible throughout the ventral striatum. There was an elegant topological correspondence between each oscillation and the underlying brain anatomy, most prominently a ~35Hz gamma-oscillation specific to the nucleus accumbens. Direct provocation of the patient's contamination obsession modulated both firing rate and gamma-oscillation amplitude within the nucleus accumbens.

  View details for DOI 10.1152/jn.00096.2019

  View details for PubMedID 31017846

• Comparative effectiveness of neuroablation and deep brain stimulation for treatment-resistant obsessive-compulsive disorder: a meta-analytic study JOURNAL OF NEUROLOGY NEUROSURGERY AND PSYCHIATRY Kumar, K. K., Appelboom, G., Lamsam, L., Caplan, A. L., Williams, N. R., Bhati, M. T., Stein, S. C., Halpern, C. H. 2019; 90 (4): 469–73

  View details for DOI 10.1136/jnnp-2018-319318

  View details for Web of Science ID 000471115600019

• Robust clinical benefit of multi-target deep brain stimulation for treatment of Gilles de la Tourette syndrome and its comorbidities. Brain stimulation Kakusa, B., Saluja, S., Tate, W. J., Espil, F. M., Halpern, C. H., Williams, N. R. 2019

  View details for PubMedID 30878341

• Interpreting Ketamine's Opioid Receptor Dependent Effect: Response to Sanacora. The American journal of psychiatry Heifets, B. D., Williams, N. R., Blasey, C., Sudheimer, K., Rodriguez, C. I., Schatzberg, A. F. 2019; 176 (3): 249–50

  View details for PubMedID 30818991

• Target Population, Dose, and Timing Considerations for Understanding Naltrexone's Subjective Effect: Response to Amiaz AMERICAN JOURNAL OF PSYCHIATRY Heifets, B. D., Williams, N. R., Blasey, C., Sudheimer, K., Rodriguez, C. I., Schatzberg, A. F. 2019; 176 (3): 251–52

  View details for DOI 10.1176/appi.ajp.2018.18111231r

  View details for Web of Science ID 000462846900013

• Interpreting Ketamine's Opioid Receptor Dependent Effect: Response to Sanacora AMERICAN JOURNAL OF PSYCHIATRY Heifets, B. D., Williams, N. R., Blasey, C., Sudheimer, K., Rodriguez, C. I., Schatzberg, A. F. 2019; 176 (3): 249–50

  View details for DOI 10.1176/appi.ajp.2018.18091061r

  View details for Web of Science ID 000462846900011

• Target Population, Dose, and Timing Considerations for Understanding Naltrexone's Subjective Effect: Response to Amiaz. The American journal of psychiatry Heifets, B. D., Williams, N. R., Blasey, C., Sudheimer, K., Rodriguez, C. I., Schatzberg, A. F. 2019; 176 (3): 251–52

  View details for PubMedID 30818989

• Comparative effectiveness of neuroablation and deep brain stimulation for treatment-resistant obsessive-compulsive disorder: a meta-analytic study. Journal of neurology, neurosurgery, and psychiatry Kumar, K. K., Appelboom, G. n., Lamsam, L. n., Caplan, A. L., Williams, N. R., Bhati, M. T., Stein, S. C., Halpern, C. H. 2019

  Abstract

  The safety and efficacy of neuroablation (ABL) and deep brain stimulation (DBS) for treatment refractory obsessive-compulsive disorder (OCD) has not been examined. This study sought to generate a definitive comparative effectiveness model of these therapies.A EMBASE/PubMed search of English-language, peer-reviewed articles reporting ABL and DBS for OCD was performed in January 2018. Change in quality of life (QOL) was quantified based on the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) and the impact of complications on QOL was assessed. Mean response of Y-BOCS was determined using random-effects, inverse-variance weighted meta-analysis of observational data.Across 56 studies, totalling 681 cases (367 ABL; 314 DBS), ABL exhibited greater overall utility than DBS. Pooled ability to reduce Y-BOCS scores was 50.4% (±22.7%) for ABL and was 40.9% (±13.7%) for DBS. Meta-regression revealed no significant change in per cent improvement in Y-BOCS scores over the length of follow-up for either ABL or DBS. Adverse events occurred in 43.6% (±4.2%) of ABL cases and 64.6% (±4.1%) of DBS cases (p<0.001). Complications reduced ABL utility by 72.6% (±4.0%) and DBS utility by 71.7% (±4.3%). ABL utility (0.189±0.03) was superior to DBS (0.167±0.04) (p<0.001).Overall, ABL utility was greater than DBS, with ABL showing a greater per cent improvement in Y-BOCS than DBS. These findings help guide success thresholds in future clinical trials for treatment refractory OCD.

  View details for PubMedID 30679237

• Adjunctive repetitive transcranial magnetic stimulation delivers superior quality of life for focal epilepsy compared to anti-epileptic drugs: A meta-analytic utility prediction study. Brain stimulation Mahajan, U. V., Parker, J. J., Williams, N. R., Bhati, M. T., Ku, S. n., Grant, G. n., Fisher, R. S., Stein, S. C., Halpern, C. H. 2019

  View details for DOI 10.1016/j.brs.2019.12.006

  View details for PubMedID 31874798

• Multimodal characterization of the human nucleus accumbens. NeuroImage Cartmell, S. C., Tian, Q. n., Thio, B. J., Leuze, C. n., Ye, L. n., Williams, N. R., Yang, G. n., Ben-Dor, G. n., Deisseroth, K. n., Grill, W. M., McNab, J. A., Halpern, C. H. 2019

  Abstract

  Dysregulation of the nucleus accumbens (NAc) is implicated in numerous neuropsychiatric disorders. Treatments targeting this area directly (e.g. deep brain stimulation) demonstrate variable efficacy, perhaps owing to non-specific targeting of a functionally heterogeneous nucleus. Here we provide support for this notion, first observing disparate behavioral effects in response to direct simulation of different locations within the NAc in a human patient. These observations motivate a segmentation of the NAc into subregions, which we produce from a diffusion-tractography based analysis of 245 young, unrelated healthy subjects. We further explore the mechanism of these stimulation-induced behavioral responses by identifying the most probable subset of axons activated using a patient-specific computational model. We validate our diffusion-based segmentation using evidence from several modalities, including MRI-based measures of function and microstructure, human post-mortem immunohistochemical staining, and cross-species comparison of cortical-NAc projections that are known to be conserved. Finally, we visualize the passage of individual axon bundles through one NAc subregion in a post-mortem human sample using CLARITY 3D histology corroborated by 7T tractography. Collectively, these findings extensively characterize human NAc subregions and provide insight into their structural and functional distinctions with implications for stereotactic treatments targeting this region.

  View details for PubMedID 31077843

• Attenuation of Antidepressant Effects of Ketamine by Opioid Receptor Antagonism Williams, N. R., Heifets, B. D., Blasey, C., Sudheimer, K., Pannu, J., Pankow, H., Hawkins, J., Birnbaum, J., Lyons, D. M., Rodriguez, C. I., Schatzberg, A. F. AMER PSYCHIATRIC PUBLISHING, INC. 2018: 1205–15

  View details for DOI 10.1176/appi.ajp.2018.18020138

  View details for Web of Science ID 000451749000012

• KETAMINE'S ANTIDEPRESSANT EFFECT IS BLOCKED BY A MU-OPIOID RECEPTOR ANTAGONIST IN HUMANS AND MICE Heifets, B. D., Williams, N., Sudheimer, K., Pankow, H., Blasey, C., Lyons, D., Schatzberg, A. F. LIPPINCOTT WILLIAMS & WILKINS. 2018: 343

  View details for Web of Science ID 000460106500197

• Closing the loop on impulsivity via nucleus accumbens delta-band activity in mice and man. Proceedings of the National Academy of Sciences of the United States of America Wu, H. n., Miller, K. J., Blumenfeld, Z. n., Williams, N. R., Ravikumar, V. K., Lee, K. E., Kakusa, B. n., Sacchet, M. D., Wintermark, M. n., Christoffel, D. J., Rutt, B. K., Bronte-Stewart, H. n., Knutson, B. n., Malenka, R. C., Halpern, C. H. 2018; 115 (1): 192–97

  Abstract

  Reward hypersensitization is a common feature of neuropsychiatric disorders, manifesting as impulsivity for anticipated incentives. Temporally specific changes in activity within the nucleus accumbens (NAc), which occur during anticipatory periods preceding consummatory behavior, represent a critical opportunity for intervention. However, no available therapy is capable of automatically sensing and therapeutically responding to this vulnerable moment in time when anticipation-related neural signals may be present. To identify translatable biomarkers for an off-the-shelf responsive neurostimulation system, we record local field potentials from the NAc of mice and a human anticipating conventional rewards. We find increased power in 1- to 4-Hz oscillations predominate during reward anticipation, which can effectively trigger neurostimulation that reduces consummatory behavior in mice sensitized to highly palatable food. Similar oscillations are present in human NAc during reward anticipation, highlighting the translational potential of our findings in the development of a treatment for a major unmet need.

  View details for PubMedID 29255043

• Transcranial Magnetic Stimulation for Disorders Other Than Depression TRANSCRANIAL MAGNETIC STIMULATION: CLINICAL APPLICATIONS FOR PSYCHIATRIC PRACTICE Pannu, J., DeSouza, D. D., Samara, Z., Raj, K. S., Williams, N. R., Lanocha, K. I., Bermudes, R. A., Lanocha, K. I., Janicak, P. G. 2018: 157–72

  View details for Web of Science ID 000549755600010

• Influence of gender on inpatient treatment for bipolar disorder: An analysis of 60,607 hospitalisations JOURNAL OF AFFECTIVE DISORDERS Fellinger, M., Waldhoer, T., Blueml, V., Williams, N., Vyssoki, B. 2018; 225: 104–7

  Abstract

  The influence of gender on inpatient treatment patterns in bipolar patients is unclear. The aim of this study is to examine whether differences in length of stay and frequency of inpatient episodes, according to ICD-10 bipolar disorder (BD)-subgroups, exist between men and women.All episodes of a manic (F31.0-2), depressive (F31.3-5) or mixed (F31.6) subtype of BD during an inpatient stay in an Austrian hospital in the period of 2001-2014 were included in this study. Data on episodes was provided by the national statistics agency. Weekly admission rates per 100,000 people were calculated by directly age-standardized rates.The database comprised 60,607 admissions (35.8% men). The number of inpatient episodes was significantly higher (p < 0.001) in women in all BD subgroups. Average length of stay in manic (p < 0.001) and depressive (p < 0.001) episodes was shorter in women compared to men. No difference could be found for mixed episodes.Only aggregated patient data and no single case histories were available for this study.The current study reveals relevant gender differences regarding inpatient treatment patterns, as women were overrepresented in all BD-subgroups. Despite equal life time prevalence, severe mood episodes lead more often to hospitalisations in women. There is a high necessity to further research the underlying causes of these findings.

  View details for PubMedID 28810176

• Modulation of the Neural Circuitry Underlying Trait Hypnotizability With Spaced Continuous Theta-Burst Stimulation Williams, N., Sudheimer, K., Stimpson, K., Duvio, D., Chung, C., DeSouza, D., Jo, B., Williams, L., Yeomans, D., Spiegel, D. NATURE PUBLISHING GROUP. 2017: S508–S509

  View details for Web of Science ID 000416846303052

• Unilateral ultra-brief pulse electroconvulsive therapy for depression in Parkinson's disease ACTA NEUROLOGICA SCANDINAVICA Williams, N. R., Bentzley, B. S., Sahlem, G. L., Pannu, J., Korte, J. E., Revuelta, G., Short, E. B., George, M. S. 2017; 135 (4): 407-411

  Abstract

  Electroconvulsive therapy (ECT) has demonstrated efficacy in treating core symptoms of Parkinson's disease (PD); however, widespread use of ECT in PD has been limited due to concern over cognitive burden. We investigated the use of a newer ECT technology known to have fewer cognitive side effects (right unilateral [RUL] ultra-brief pulse [UBP]) for the treatment of medically refractory psychiatric dysfunction in PD.This open-label pilot study included 6 patients who were assessed in the motoric, cognitive, and neuropsychiatric domains prior to and after RUL UBP ECT. Primary endpoints were changes in total score on the HAM-D-17 and GDS-30 rating scales.Patients were found to improve in motoric and psychiatric domains following RUL UBP ECT without cognitive side effects, both immediately following ECT and at 1-month follow-up.This study demonstrates that RUL UBP ECT is safe, feasible, and potentially efficacious in treating multiple domains of PD, including motor and mood, without clear cognitive side effects.

  View details for DOI 10.1111/ane.12614

  View details for Web of Science ID 000398035900004

  View details for PubMedCentralID PMC5133197

• It takes time to tune ANNALS OF TRANSLATIONAL MEDICINE Bentzley, B. S., Pannu, J., Badran, B. W., Halpern, C. H., Williams, N. R. 2017; 5 (7): 171

  View details for PubMedID 28480207

  View details for PubMedCentralID PMC5401673

• Neuroversion: using electroconvulsive therapy as a bridge to deep brain stimulation implantation NEUROCASE Williams, N. R., Sahlem, G., Pannu, J., Takacs, I., Short, B., Revuelta, G., George, M. S. 2017; 23 (1): 26-30

  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.

  View details for DOI 10.1080/13554794.2016.1276605

  View details for Web of Science ID 000399644200005

  View details for PubMedID 28376692

• It Takes Time to Tune Annals of Translational Medicine Bentzley, B. S., Pannu, J., Badran, B. W., Halpern, C. H., Williams, N. R. 2017; In Press
• Optimization of epidural cortical stimulation for treatment-resistant depression. Brain stimulation Williams, N. R., Bentzley, B. S., Hopkins, T. n., Pannu, J. n., Sahlem, G. L., Takacs, I. n., George, M. S., Nahas, Z. n., Short, E. B. 2017

  View details for PubMedID 28918944

• Description of a Novel, Surgically Implanted Neuromodulatory Technique Known as Bilateral Epidural Prefrontal Cortical Stimulation (EpCS) for Treatment-Resistant Depression (TRD) Journal of Visualized Experiments Williams, N. R., Pannu, J., Bentzley, B. B., Hopkins, T., Badran, B. W., Short, E., George, M. S., Takacs, I., Nahas, Z. 2017; In Press
• Unilateral ultra-brief pulse electroconvulsive therapy for depression in Parkinson's disease. Acta neurologica Scandinavica Williams, N. R., Bentzley, B. S., Sahlem, G. L., Pannu, J., Korte, J. E., Revuelta, G., Short, E. B., George, M. S. 2016

  Abstract

  Electroconvulsive therapy (ECT) has demonstrated efficacy in treating core symptoms of Parkinson's disease (PD); however, widespread use of ECT in PD has been limited due to concern over cognitive burden. We investigated the use of a newer ECT technology known to have fewer cognitive side effects (right unilateral [RUL] ultra-brief pulse [UBP]) for the treatment of medically refractory psychiatric dysfunction in PD.This open-label pilot study included 6 patients who were assessed in the motoric, cognitive, and neuropsychiatric domains prior to and after RUL UBP ECT. Primary endpoints were changes in total score on the HAM-D-17 and GDS-30 rating scales.Patients were found to improve in motoric and psychiatric domains following RUL UBP ECT without cognitive side effects, both immediately following ECT and at 1-month follow-up.This study demonstrates that RUL UBP ECT is safe, feasible, and potentially efficacious in treating multiple domains of PD, including motor and mood, without clear cognitive side effects.

  View details for DOI 10.1111/ane.12614

  View details for PubMedID 27241213

  View details for PubMedCentralID PMC5133197

• Stimulating Across the Frontostriatal Circuitry to Treat Parkinson's Disease Williams, N. R., Short, E., Bentzley, B., Pannu, J., Sahlem, G., Hanlon, C., Korte, J., Revuelta, G., George, M. ELSEVIER SCIENCE INC. 2016: 402S–403S

  View details for Web of Science ID 000432440805134

• Neuroversion: Using Electroconvulsive Therapy as a Bridge to Deep Brain Stimulation Implantation Williams, N. R., Sahlem, G., Jeffey, B., Pannu, J., Takacs, I., Revuelta, G., George, M. ELSEVIER SCIENCE INC. 2016: 127S–128S

  View details for Web of Science ID 000432440801153

• Reward circuit DBS improves Parkinson's gait along with severe depression and OCD NEUROCASE Williams, N. R., Hopkins, T. R., Short, E. B., Sahlem, G. L., Snipes, J., Revuelta, G. J., George, M. S., Takacs, I. 2016; 22 (2): 201-204

  Abstract

  A 59-year-old Caucasian man with a past history of Parkinson's disease (PD) status post-bilateral subthalamic nucleus (STN) deep brain stimulation (DBS), who also had treatment-resistant (TR) obsessive-compulsive disorder (OCD), and treatment-resistant depression (TRD), presented for further evaluation and management of his TR OCD. After an unsuccessful attempt to treat his OCD by reprogramming his existing STN DBS, he was offered bilateral ventral capsule/ventral striatum (VC/VS) DBS surgery. In addition to the expected improvement in OCD symptoms, he experienced significant improvement in both PD-related apathy and depression along with resolution of suicidal ideation. Furthermore, the patient's festinating gait dramatically improved. This case demonstrates that DBS of both the STN and VC/VS appears to have an initial signal of safety and tolerability. This is the first instance where both the STN and the VC/VS DBS targets have been implanted in an individual and the first case where a patient with PD has received additional DBS in mood-regulatory circuitry.

  View details for DOI 10.1080/13554794.2015.1112019

  View details for Web of Science ID 000369770400011

  View details for PubMedID 26644268

• NMDA antagonist treatment of depression. Current opinion in neurobiology Williams, N. R., Schatzberg, A. F. 2016; 36: 112-117

  Abstract

  Ketamine is a psychoactive anesthetic agent, which has been approved and utilized for various forms of anesthesia over decades. Recently, ketamine has been demonstrated to have robust and rapid antidepressant effects in individuals with treatment-resistant depression. After more than a decade of research, it is unclear what the mechanisms underlying the novel antidepressant effect are. The consensus has centered on NMDA properties of ketamine as a potential factor in the mechanism for antidepressant action. However, this may be a true but partial explanation of the effects of ketamine as a novel antidepressant. It appears that ketamine influences synaptic plasticity and may promote new synapse formation. From a neurocircuitry perspective, ketamine may exert some of its effects on the anterior cingulate.

  View details for DOI 10.1016/j.conb.2015.11.001

  View details for PubMedID 26687375

• Beyond Neural Cubism: Promoting a Multidimensional View of Brain Disorders by Enhancing the Integration of Neurology and Psychiatry in Education ACADEMIC MEDICINE Taylor, J. J., Williams, N. R., George, M. S. 2015; 90 (5): 581-586

  Abstract

  Cubism was an influential early-20th-century art movement characterized by angular, disjointed imagery. The two-dimensional appearance of Cubist figures and objects is created through juxtaposition of angles. The authors posit that the constrained perspectives found in Cubism may also be found in the clinical classification of brain disorders. Neurological disorders are often separated from psychiatric disorders as if they stemmed from different organ systems. Maintaining two isolated clinical disciplines fractionalizes the brain in the same way that Pablo Picasso fractionalized figures and objects in his Cubist art. This Neural Cubism perpetuates a clinical divide that does not reflect the scope and depth of neuroscience. All brain disorders are complex and multidimensional, with aberrant circuitry and resultant psychopharmacology manifesting as altered behavior, affect, mood, or cognition. Trainees should receive a multidimensional education based on modern neuroscience, not a partial education based on clinical precedent. The authors briefly outline the rationale for increasing the integration of neurology and psychiatry and discuss a nested model with which clinical neuroscientists (neurologists and psychiatrists) can approach and treat brain disorders.

  View details for DOI 10.1097/ACM.0000000000000530

  View details for Web of Science ID 000353879700016

  View details for PubMedID 25340364

  View details for PubMedCentralID PMC4405399

• Oscillating Square Wave Transcranial Direct Current Stimulation (tDCS) Delivered During Slow Wave Sleep Does Not Improve Declarative Memory More Than Sham: A Randomized Sham Controlled Crossover Study BRAIN STIMULATION Sahlem, G. L., Badran, B. W., Halford, J. J., Williams, N. R., Korte, J. E., Leslie, K., Strachan, M., Breedlove, J. L., Runion, J., Bachman, D. L., Uhde, T. W., Borckardt, J. J., George, M. S. 2015; 8 (3): 528-534

  Abstract

  A 2006 trial in healthy medical students found that anodal slow oscillating tDCS delivered bi-frontally during slow wave sleep had an enhancing effect in declarative, but not procedural memory. Although there have been supporting animal studies, and similar findings in pathological groups, this study has not been replicated, or refuted, in the intervening years. We therefore tested these earlier results for replication using similar methods with the exception of current waveform (square in our study, nearly sinusoidal in the original).Our objective was to test the findings of a 2006 trial suggesting bi-frontal anodal tDCS during slow wave sleep enhances declarative memory.Twelve students (mean age 25, 9 women) free of medical problems underwent two testing conditions (active, sham) in a randomized counterbalanced fashion. Active stimulation consisted of oscillating square wave tDCS delivered during early Non-Rapid Eye Movement (NREM) sleep. The sham condition consisted of setting-up the tDCS device and electrodes, but not turning it on during sleep. tDCS was delivered bi-frontally with anodes placed at F3/F4, and cathodes placed at mastoids. Current density was 0.517 mA/cm(2), and oscillated between zero and maximal current at a frequency of 0.75 Hz. Stimulation occurred during five-five minute blocks with 1-min inter-block intervals (25 min total stimulation). The primary outcomes were both declarative memory consolidation measured by a paired word association test (PWA), and non-declarative memory, measured by a non-dominant finger-tapping test (FTT). We also recorded and analyzed sleep EEG.There was no difference in the number of paired word associations remembered before compared to after sleep [(active = 3.1 ± 3.0 SD more associations) (sham = 3.8 ± 3.1 SD more associations)]. Finger tapping improved, (non-significantly) following active stimulation [(3.6 ± 2.7 SD correctly typed sequences) compared to sham stimulation (2.3 ± 2.2 SD correctly typed sequences)].In this study, we failed to find improvements in declarative or performance memory and could not replicate an earlier study using nearly identical settings. Specifically we failed to find a beneficial effect on either overnight declarative or non-declarative memory consolidation via square-wave oscillating tDCS intervention applied bi-frontally during early NREM sleep. It is unclear if the morphology of the tDCS pulse is critical in any memory related improvements.

  View details for DOI 10.1016/j.brs.2015.01.414

  View details for Web of Science ID 000355772300013

  View details for PubMedID 25795621

  View details for PubMedCentralID PMC4598642

• Adjunctive triple chronotherapy (combined total sleep deprivation, sleep phase advance, and bright light therapy) rapidly improves mood and suicidality in suicidal depressed inpatients: An open label pilot study JOURNAL OF PSYCHIATRIC RESEARCH Sahlem, G. L., Kalivas, B., Fox, J. B., Lamb, K., Roper, A., Williams, E. N., Williams, N. R., Korte, J. E., Zuschlag, Z. D., El Sabbagh, S., Guille, C., Barth, K. S., Uhde, T. W., George, M. S., Short, E. B. 2014; 59: 101-107

  Abstract

  Previous studies have demonstrated that combined total sleep deprivation (Wake therapy), sleep phase advance, and bright light therapy (Triple Chronotherapy) produce a rapid and sustained antidepressant effect in acutely depressed individuals. To date no studies have explored the impact of the intervention on unipolar depressed individuals with acute concurrent suicidality. Participants were suicidal inpatients (N = 10, Mean age = 44 ± 16.4 SD, 6F) with unipolar depression. In addition to standard of care, they received open label Triple Chronotherapy. Participants underwent one night of total sleep deprivation (33-36 h), followed by a three-night sleep phase advance along with four 30-min sessions of bright light therapy (10,000 lux) each morning. Primary outcome measures included the 17 item Hamilton depression scale (HAM17), and the Columbia Suicide Severity Rating Scale (CSSRS), which were recorded at baseline prior to total sleep deprivation, and at protocol completion on day five. Both HAM17, and CSSRS scores were greatly reduced at the conclusion of the protocol. HAM17 scores dropped from a mean of 24.7 ± 4.2 SD at baseline to a mean of 9.4 ± 7.3 SD on day five (p = .002) with six of the ten individuals meeting criteria for remission. CSSRS scores dropped from a mean of 19.5 ± 8.5 SD at baseline to a mean of 7.2 ± 5.5 SD on day five (p = .01). The results of this small pilot trial demonstrate that adjunctive Triple Chronotherapy is feasible and tolerable in acutely suicidal and depressed inpatients. Limitations include a small number of participants, an open label design, and the lack of a comparison group. Randomized controlled studies are needed.

  View details for DOI 10.1016/j.jpsychires.2014.08.015

  View details for Web of Science ID 000344205700014

  View details for PubMedID 25231629

  View details for PubMedCentralID PMC4252537

• Role of functional imaging in the development and refinement of invasive neuromodulation for psychiatric disorders. World journal of radiology Williams, N. R., Taylor, J. J., Lamb, K., Hanlon, C. A., Short, E. B., George, M. S. 2014; 6 (10): 756-778

  Abstract

  Deep brain stimulation (DBS) is emerging as a powerful tool for the alleviation of targeted symptoms in treatment-resistant neuropsychiatric disorders. Despite the expanding use of neuropsychiatric DBS, the mechanisms responsible for its effects are only starting to be elucidated. Several modalities such as quantitative electroencephalography as well a intraoperative recordings have been utilized to attempt to understand the underpinnings of this new treatment modality, but functional imaging appears to offer several unique advantages. Functional imaging techniques like positron emission tomography, single photon emission computed tomography and functional magnetic resonance imaging have been used to examine the effects of focal DBS on activity in a distributed neural network. These investigations are critical for advancing the field of invasive neuromodulation in a safe and effective manner, particularly in terms of defining the neuroanatomical targets and refining the stimulation protocols. The purpose of this review is to summarize the current functional neuroimaging findings from neuropsychiatric DBS implantation for three disorders: treatment-resistant depression, obsessive-compulsive disorder, and Tourette syndrome. All of the major targets will be discussed (Nucleus accumbens, anterior limb of internal capsule, subcallosal cingulate, Subthalamic nucleus, Centromedial nucleus of the thalamus-Parafasicular complex, frontal pole, and dorsolateral prefrontal cortex). We will also address some apparent inconsistencies within this literature, and suggest potential future directions for this promising area.

  View details for DOI 10.4329/wjr.v6.i10.756

  View details for PubMedID 25349661

  View details for PubMedCentralID PMC4209423

• Interventional Psychiatry: Why Now? JOURNAL OF CLINICAL PSYCHIATRY Williams, N. R., Taylor, J. J., Kerns, S., Short, E. B., Kantor, E. M., George, M. S. 2014; 75 (8): 895-897

  Abstract

  Interventional psychiatry offers substantial therapeutic benefits in some neuropsychiatric disorders and enormous potential in treating others. However, as interventional diagnostics and therapeutics require specialized knowledge and skill foreign to many psychiatrists, the emerging subspecialty of interventional psychiatry must be more formally integrated into the continuum of psychiatric training to ensure both safe application and continued growth. By establishing training paradigms for interventional psychiatry, academic medical centers can help fill this knowledge gap. The cultivation of a properly trained cohort of interventional psychiatrists will better meet the challenges of treatment-resistant psychiatric illness through safe and ethical practice, while facilitating a more informed development and integration of novel neuromodulation techniques.

  View details for DOI 10.4088/JCP.13l08745

  View details for Web of Science ID 000345530300019

  View details for PubMedID 25191910

  View details for PubMedCentralID PMC4221242

• Interventional Psychiatry: How Should Psychiatric Educators Incorporate Neuromodulation into Training? ACADEMIC PSYCHIATRY Williams, N. R., Taylor, J. J., Snipes, J. M., Short, E. B., Kantor, E. M., George, M. S. 2014; 38 (2): 168-176

  Abstract

  Interventional psychiatry is an emerging subspecialty that uses a variety of procedural neuromodulation techniques in the context of an electrocircuit-based view of mental dysfunction as proximal causes for psychiatric diseases.The authors propose the development of an interventional psychiatry-training paradigm analogous to those found in cardiology and neurology.The proposed comprehensive training in interventional psychiatry would include didactics in the theory, proposed mechanisms, and delivery of invasive and noninvasive brain stimulation.The development and refinement of this subspecialty would facilitate safe, effective growth in the field of brain stimulation by certified and credentialed practitioners within the field of psychiatry while also potentially improving the efficacy of current treatments.

  View details for DOI 10.1007/s40596-014-0050-x

  View details for Web of Science ID 000334414300012

  View details for PubMedID 24554501

  View details for PubMedCentralID PMC4021584

• STN vs. GPi Deep Brain Stimulation: Translating the Rematch into Clinical Practice. Movement disorders clinical practice Williams, N. R., Foote, K. D., Okun, M. S. 2014; 1 (1): 24-35

  Abstract

  When formulating a deep brain stimulation (DBS) treatment plan for a patient with Parkinson's disease (PD), two critical questions should be addressed: 1- Which brain target should be chosen to optimize this patient's outcome? and 2- Should this patient's DBS operation be unilateral or bilateral? Over the past two decades, two targets have emerged as leading contenders for PD DBS; the subthalamic nucleus (STN) and the globus pallidus internus (GPi). While the GPi target does have a following, most centers have uniformly employed bilateral STN DBS for all Parkinson's disease cases (Figure 1). This bilateral STN "one-size-fits-all" approach was challenged by an editorial entitled "STN vs. GPi: The Rematch," which appeared in the Archives of Neurology in 2005. Since 2005, a series of well designed clinical trials and follow-up studies have addressed the question as to whether a more tailored approach to DBS therapy might improve overall outcomes. Such a tailored approach would include the options of targeting the GPi, or choosing a unilateral operation. The results of the STN vs. GPi 'rematch' studies support the conclusion that bilateral STN DBS may not be the best option for every Parkinson's disease surgical patient. Off period motor symptoms and tremor improve in both targets, and with either unilateral or bilateral stimulation. Advantages of the STN target include more medication reduction, less frequent battery changes, and a more favorable economic profile. Advantages of GPi include more robust dyskinesia suppression, easier programming, and greater flexibility in adjusting medications. In cases where unilateral stimulation is anticipated, the data favor GPi DBS. This review summarizes the accumulated evidence regarding the use of bilateral vs. unilateral DBS and the selection of STN vs. GPi DBS, including definite and possible advantages of different targets and approaches. Based on this evidence, a more patient-tailored, symptom specific approach will be proposed to optimize outcomes of PD DBS therapy. Finally, the importance of an interdisciplinary care team for screening and effective management of DBS patients will be reaffirmed. Interdisciplinary teams can facilitate the proposed patient-specific DBS treatment planning and provide a more thorough analysis of the risk-benefit ratio for each patient.

  View details for DOI 10.1002/mdc3.12004

  View details for PubMedID 24779023

  View details for PubMedCentralID PMC4000041

• Incidence of sport-related traumatic brain injury and risk factors of severity: a population-based epidemiologic study ANNALS OF EPIDEMIOLOGY Selassie, A. W., Wilson, D. A., Pickelsimer, E. E., Voronca, D. C., Williams, N. R., Edwards, J. C. 2013; 23 (12): 750-756

  Abstract

  Few studies of sport-related traumatic brain injury (TBI) are population-based or rely on directly observed data on cause, demographic characteristics, and severity. This study addresses the epidemiology of sport-related TBI in a large population.Data on all South Carolina hospital and emergency department encounters for TBI, 1998-2011, were analyzed. Annual incidence rate of sport-related TBI was calculated, and rates were compared across demographic groups. Sport-related TBI severity was modeled as a function of demographic and TBI characteristics using logistic regression.A total of 16,642 individuals with sport-related TBI yielded an average annual incidence rate of 31.5/100,000 population with a steady increase from 19.7 in 1998 to 45.6 in 2011. The most common mechanisms of sport-related TBI were kicked in football (38.1%), followed by fall injuries in sports (20.3%). Incidence rate was greatest in adolescents ages 12-18 (120.6/100,000/persons). Severe sport-related TBI was strongly associated with off-road vehicular sport (odds ratio [OR], 4.73; 95% confidence interval [95% CI], 2.92-7.67); repeated head trauma (OR, 4.36; 95% CI, 3.69-5.15); equestrian sport (OR, 2.73; 95% CI, 1.64-4.51); and falls during sport activities (OR, 2.72; 95% CI, 1.67-4.46).The high incidence of sport-related TBI in youth, potential for repetitive mild TBI, and its long-term consequences on learning warrants coordinated surveillance activities and population-based outcome studies.

  View details for DOI 10.1016/j.annepidem.2013.07.022

  View details for Web of Science ID 000327926100002

  View details for PubMedID 24060276

  View details for PubMedCentralID PMC4021712

• Unique Case of "Post-Lumbar Puncture Headache" HEADACHE Patel, B. A., Williams, N. R., Pritchard, P. B. 2013; 53 (9): 1479-1481

  Abstract

  Lumbar puncture (LP) is associated with complications that include post-LP orthostatic headache, local bleeding, and subdural hematoma. We report a unique case of a spontaneous frontal epidural hematoma following a therapeutic lumbar puncture in a patient with a history of idiopathic intracranial hypertension. This case highlights the importance of symptomatology in patients following LPs by revealing a rare intracranial presentation that would be devastating if not discovered promptly and appropriately managed.

  View details for DOI 10.1111/head.12005

  View details for Web of Science ID 000325156600008

  View details for PubMedID 23298181

  View details for PubMedCentralID PMC4048948

• Sports-Related Concussions PEDIATRIC EMERGENCY CARE Upshaw, J. E., Gosserand, J. K., Williams, N., Edwards, J. C. 2012; 28 (9): 926-935

  Abstract

  During the past decade, awareness of concussions has exploded as both the media and the medical literature have given more focus to this common problem. Concussions after recreational activities, especially athletics, are a frequent complaint in the emergency department. In the past few years, care of these patients has been simplified as grading systems and classifications have been abandoned. However, questions remain as to the best way to rehabilitate these patients to avoid long-term sequelae, especially in children and adolescents. The purpose of this review is to discuss the demographic characteristics, the pathophysiology, definition, clinical characteristics, and management of concussions in children and adolescents.

  View details for DOI 10.1097/PEC.0b013e318267f674

  View details for Web of Science ID 000308673600023

  View details for PubMedID 22940896

• High school coaches perceptions of physicians' role in the assessment and management of sports-related concussive injury. Frontiers in neurology Williams, N., Sas, A., Madey, J., Bodle, J., Scovel, L., Edwards, J. 2012; 3: 130-?

  Abstract

  Sports concussions are an increasingly recognized common type of mild traumatic brain injury (TBI) that affect athletes of all ages. The need for an increased involvement of trained physicians in the diagnosis and treatment of concussion has become more obvious as the pathophysiology and long-term sequelae of sports concussion are better understood. To date, there has been great variability in the athletic community about the recognition of symptoms, diagnosis, management, and physician role in concussion care. An awareness assessment survey administered to 96 high school coaches in a large metropolitan city demonstrated that 37.5% of responders refer their concussed players to an emergency department after the incident, only 39.5% of responders have a physician available to evaluate their players after a concussion, 71.6% of those who had a physician available sent their players to a sports medicine physician, and none of the responders had their player's concussion evaluated by a neurologist. Interestingly, 71.8% of responders stated that their players returned to the team with "return to play" guidelines from their physician. This survey has highlighted two important areas where the medical community can better serve the athletic community. Because a concussion is a sport-inflicted injury to the nervous system, it is optimally evaluated and managed by a clinician with relevant training in both clinical neuroscience and sports medicine. Furthermore, all physicians who see patients suffering concussion should be educated in the current recommendations from the Consensus Statement on Concussion and provide return to play instructions that outline a graduated return to play, allowing the athlete to return to the field safely.

  View details for DOI 10.3389/fneur.2012.00130

  View details for PubMedID 23060851

  View details for PubMedCentralID PMC3464423

• Diagnosis, Treatment, and Long-Term Outcomes of Late-Onset (Type III) Multiple Acyl-CoA Dehydrogenase Deficiency JOURNAL OF CHILD NEUROLOGY Pollard, L. M., Williams, N. R., Espinoza, L., Wood, T. C., Spector, E. B., Schroer, R. J., Holden, K. R. 2010; 25 (8): 954-960

  Abstract

  We report 4 children with late-onset (type III) multiple acyl-CoA dehydrogenase deficiency, also known as glutaric aciduria type II, which is an autosomal recessive disorder of fatty acid and amino acid metabolism. The underlying deficiency is in the electron transfer flavoprotein or electron flavoprotein dehydrogenase. Clinical presentations include fatal acute neonatal metabolic encephalopathies with/without organ system anomalies (types I and II) and late-onset acute metabolic crises, myopathy, or neurodevelopmental delays (type III). Two patients were identified in childhood following a metabolic crisis and/or neurodevelopmental delay, and 2 were identified by newborn metabolic screening. Our cases will illustrate the difficulty in making a biochemical diagnosis of late-onset (type III) multiple acyl-CoA dehydrogenase deficiency from plasma acylcarnitines and urine organic acids in both symptomatic and asymptomatic children. However, they emphasize the need for timely diagnosis to urgently implement prophylactic treatment for life-threatening metabolic crises with low protein/fat diets supplemented with riboflavin and carnitine.

  View details for DOI 10.1177/0883073809351984

  View details for Web of Science ID 000279908100003

  View details for PubMedID 20023066

• Relapse rates with long-term antidepressant drug therapy: a meta-analysis HUMAN PSYCHOPHARMACOLOGY-CLINICAL AND EXPERIMENTAL Williams, N., Simpson, A. N., Simpson, K., Nahas, Z. 2009; 24 (5): 401-408

  Abstract

  Several long-term double-blind placebo controlled trials have shown prophylactic antidepressant therapy in unipolar depression. The goal of this work was to conduct a meta-analysis that would incorporate the most recent trials and evaluate their overall level of efficacy and relapse prevention over time.We performed a comprehensive literature search. The extracted data from selected studies were used to construct a regression model and evaluate the effect of treatment, time on medication, severity of illness, age, gender, and number of previous episodes.Across 11 maintenance treatment studies, the relapse rate was significantly different at 1 year for active drug (23%) versus placebo (51%). In addition, time on medication significantly affected the relapse rate.Prophylactic antidepressant drug therapy appears efficacious in preventing future relapses across a range of illness severity as well as age. More studies are needed to explore the effects of various acute antidepressant strategies and the direct influence of treatment resistance on relapse outcomes.

  View details for DOI 10.1002/hup.1033

  View details for Web of Science ID 000268116900004

  View details for PubMedID 19526453