Nolan R. Williams

Deep brain stimulation (DBS) at the interface of neurology and psychiatry

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.

Subthalamic Nucleus Versus Globus Pallidus Internus Deep Brain Stimulation: Translating the Rematch Into Clinical Practice

When formulating a DBS treatment plan for a patient with Parkinsons disease (PD), two critical questions should be addressed: (1) Which brain target should be chosen to optimize this patients outcome? and (2) Should this patients DBS operation be uni‐ or bilateral? Over the past two decades, two targets have emerged as leading contenders for PD DBS; the STN and the globus pallidus internus (GPi). Whereas the GPi target does have a following, most centers have uniformly employed bilateral STN DBS for all PD cases. This bilateral STN “one‐size‐fits‐all” approach was challenged by an editorial entitled “STN versus 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 versus GPi “rematch” studies support the conclusion that bilateral STN DBS may not be the best option for every PD surgical patient. Off‐period motor symptoms and tremor improve in both targets as well as with either uni‐ 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 use of bi‐ versus unilateral DBS and selection of STN versus 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.

Relapse rates with long‐term antidepressant drug therapy: a meta‐analysis

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.

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

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.

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.

BACKGROUND 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). OBJECTIVE/HYPOTHESIS Our objective was to test the findings of a 2006 trial suggesting bi-frontal anodal tDCS during slow wave sleep enhances declarative memory. METHODS 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. RESULTS 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)]. CONCLUSION 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.

NMDA antagonist treatment of depression.

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.

Interventional psychiatry: how should psychiatric educators incorporate neuromodulation into training?

ObjectiveInterventional 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.MethodsThe authors propose the development of an interventional psychiatry-training paradigm analogous to those found in cardiology and neurology.ResultsThe proposed comprehensive training in interventional psychiatry would include didactics in the theory, proposed mechanisms, and delivery of invasive and noninvasive brain stimulation.ConclusionsThe 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.

Sports-related concussions

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.

Diagnosis, Treatment, and Long-Term Outcomes of Late-Onset (Type III) Multiple Acyl-CoA Dehydrogenase Deficiency

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.

Closing the loop on impulsivity via nucleus accumbens delta-band activity in mice and man

Significance We reveal prominent delta oscillations in the nucleus accumbens preceding food reward in mice and use them to guide responsive neurostimulation to suppress binge-like behavior. Similar electrographic signatures are observed in human nucleus accumbens during reward anticipation as well, suggesting their translational potential in the development of a treatment for loss of impulse control in obesity and perhaps additional brain disorders. 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.