Deep brain stimulation programming for intractable obsessive-compulsive disorder using a long pulse width.

Introduction: Around 25% of patients with obsessive-compulsive disorder (OCD) do not respond to medication or psychotherapy, producing significant impairment and treatment challenges. Deep Brain Stimulation (DBS) has been shown in multiple blinded trials to be a safe and durable emerging option for treatment-refractory OCD. Intraoperative device interrogation offers a theoretical anchor for starting outpatient DBS programming; however, no definitive post-operative programming algorithm for psychiatrists exists currently. Case: Here we present a 58-year-old female with childhood-onset, severe, intractable OCD with multiple failed trials of psychotherapy, medication, and electroconvulsive therapy. After interdisciplinary evaluation, she underwent bilateral electrode implantation targeting the anterior limb of the internal capsule, nucleus accumbens (ALIC/NAc). Intraoperative interrogation afforded sparse information about a preferred lead contact or current density target. Subsequent outpatient interrogation consisted of systematic and independent mapping using monopolar cathodic stimulation with constant current. Modulating bipolar and triple monopolar configurations, amplitude, and pulse width all failed to induce observable effects. Given negligible interrogation feedback, we created an electrical field through the ALIC bilaterally, using the three most ventral contacts to create triple monopoles, with a long pulse width and moderate amperage. Conclusion: Three months post-programming, the patient reported significant improvement in OCD symptoms, particularly checking behaviors, with response sustained over the next several months. As with our case, the majority of DBS lead contacts do not induce affective or physiological markers in patients, complicating programming optimization. Here, we discuss an approach to titrating various stimulation parameters and purported mechanisms of physiological markers in DBS for OCD.

Rapid symptom control in neuroleptic malignant syndrome with electroconvulsive therapy: A case report.

Introduction: Neuroleptic malignant syndrome (NMS), thought to arise through dopamine antagonism, is life-threatening. While prompt diagnosis of NMS is critical, it may be obscured by other diagnoses, such as malignant catatonia, with overlapping, life-threatening symptoms. Initiation of dopamine-blocking agents such as antipsychotics and abrupt cessation of dopaminergic medications such as amantadine can precipitate NMS. Once NMS is suspected, deft medical management should ensue. Multiple case reports detail electroconvulsive therapy's (ECT's) effectiveness in the treatment of NMS. While this relationship is well-documented, there is less literature regarding comparative efficacy of ECT in the acute treatment of NMS-like states precipitated by withdrawal of dopamine agonists, such as amantadine. Case: We present a 52-year-old female with schizoaffective disorder bipolar type, with a history of a lorazepam-resistant catatonic episode the prior year that had responded to amantadine. She presented febrile with altered mental status, lead pipe rigidity, mutism, grasp reflex, stereotypy, autonomic instability, and a Bush-Francis Catatonia Rating Scale (BFCRS) of 24, suggesting malignant catatonia versus NMS. There was concern over a potentially abrupt cessation of her amantadine of which she had been prescribed for the past year. Interventions: Organic etiologies were ruled out, and a presumptive diagnosis of NMS was made with central dopaminergic depletion from abrupt dopamine agonist (amantadine) withdrawal as the suspected underlying etiology. After intravenous lorazepam and reinduction of amantadine failed to alleviate her symptoms, urgent ECT was initiated. Our patient received an index series of ECT of seven treatments. After ECT #1 she was no longer obtunded, after treatment #2 her symptoms of mutism, rigidity, stereotypy, and agitation showed improvement, and by ECT #3, the NMS had rapidly dissipated as evidenced by stable vital signs, lack of rigidity, and coherent conversation. Conclusion: Brisk identification of potentially life-threatening NMS and NMS-like states, including malignant catatonia, warrants a trial of ECT. ECT's theoretical mechanisms of action coincide with the theoretical pathophysiology of the conditions. It is a viable and safe treatment option for reducing mortality. With prompt initiation of ECT, we obtained rapid control of a condition with a potentially high mortality.

Cerebral revascularization surgery reduces cerebrovascular events in children with sickle cell disease and moyamoya syndrome: Results of the stroke in sickle cell revascularization surgery retrospective study.

BACKGROUND: Recent studies suggest that cerebral revascularization surgery may be a safe and effective therapy to reduce stroke risk in patients with sickle cell disease and moyamoya syndrome (SCD-MMS). METHODS: We performed a multicenter, retrospective study of children with SCD-MMS treated with conservative management alone (conservative group)-chronic blood transfusion and/or hydroxyurea-versus conservative management plus surgical revascularization (surgery group). We monitored cerebrovascular event (CVE) rates-a composite of strokes and transient ischemic attacks. Multivariable logistic regression was used to compare CVE occurrence and multivariable Poisson regression was used to compare incidence rates between groups. Covariates in multivariable models included age at treatment start, age at moyamoya diagnosis, antiplatelet use, CVE history, and the risk period length. RESULTS: We identified 141 patients with SCD-MMS, 78 (55.3%) in the surgery group and 63 (44.7%) in the conservative group. Compared with the conservative group, preoperatively the surgery group had a younger age at moyamoya diagnosis, worse baseline modified Rankin scale scores, and increased prevalence of CVEs. Despite more severe pretreatment disease, the surgery group had reduced odds of new CVEs after surgery (odds ratio = 0.27, 95% confidence interval [CI] = 0.08-0.94, p = .040). Furthermore, comparing surgery group patients during presurgical versus postsurgical periods, CVEs odds were significantly reduced after surgery (odds ratio = 0.22, 95% CI = 0.08-0.58, p = .002). CONCLUSIONS: When added to conservative management, cerebral revascularization surgery appears to reduce the risk of CVEs in patients with SCD-MMS. A prospective study will be needed to validate these findings.

Case report: Rapid symptom resolution of a mixed affective state with high-frequency repetitive transcranial magnetic stimulation.

Introduction: Bipolar major depressive episodes with mixed features are diagnosed in patients who meet the full criteria for a major depressive episode exhibiting three additional concurrent symptoms of hypomania or mania. Up to half of patients with bipolar disorder experience mixed episodes, which are more likely to be treatment-refractory than pure depression or mania/hypomania alone. Case: We present a 68-year-old female with Bipolar Type II Disorder with a four-month medication-refractory major depressive episode with mixed features referred for neuromodulation consultation. Previous failed medication trials over several years included lithium, valproate, lamotrigine, topiramate, and quetiapine. She had no history of treatment with neuromodulation. At the initial consultation, her baseline Montgomery-Asberg Depression Rating Scale (MADRS) was moderate in severity at 32. Her Young Mania Rating Scale (YMRS) was 22, with dysphoric hypomanic symptoms consisting of heightened irritability, verbosity and increased rate of speech, and decreased sleep. She declined electroconvulsive therapy but elected to receive repetitive transcranial magnetic stimulation (rTMS). Interventions: The patient underwent repetitive transcranial magnetic stimulation (rTMS) with a Neuronetics NeuroStar system, receiving nine daily sessions over the left dorsolateral prefrontal cortex (DLPFC). Standard settings of 120% MT, 10 Hz (4 sec on, 26 sec off), and 3,000 pulses/session were used. Her acute symptoms showed a brisk response, and at the final treatment, her repeat MADRS was 2, and YMRS was 0. The patient reported feeling "great," which she defined as feeling stable with minimal depression and hypomania for the first time in years. Conclusion: Mixed episodes present a treatment challenge given their limited treatment options and diminished responses. Previous research has shown decreased efficacy of lithium and antipsychotics in mixed episodes with dysphoric mood such as the episode our patient experienced. One open-label study of low-frequency right-sided rTMS showed promising results in patients with treatment-refractory depression with mixed features, but the role of rTMS in the management of these episodes is largely unexplored. Given the concern for potential manic mood switches, further investigation into the laterality, frequency, anatomical target, and efficacy of rTMS for bipolar major depressive episodes with mixed features is warranted.

Electroconvulsive therapy use for refractory status epilepticus in an implantable vagus nerve stimulation patient: A case report.

Introduction: Status epilepticus (SE) has a mortality rate of 20 to 50%, with acute symptomatic SE having a higher risk compared to chronic SE. Electroconvulsive therapy (ECT) has been utilized for the treatment of refractory SE with a success rate estimate of 57.9%. There are no known reported cases of concomitant use of vagus nerve stimulation (VNS) and ECT for the treatment of super refractory SE (SRSE) available in the literature. Case description: We present a 44-year-old female with a history of developmental delay, epilepsy, an implantable VNS for 6 years, and traumatic brain injury with subsequent hygroma who presented with progressive aphasia, declining mental status, and daily generalized seizures lasting up to 20 min. Seizures had increased from her baseline of one seizure per day controlled with topiramate 200 mg three times daily and lamotrigine 400 mg twice daily. She was diagnosed with SRSE after being intubated and placed on eight anti-epileptic drugs (AEDs) that failed to abort SE. ECT was attempted to terminate SE. Due to a prior right craniotomy with subsequent right hygroma, eight treatments of ECT were performed over three sessions using a right anterior, left temporal (RALT) and subsequently a bitemporal electrode placement. The VNS remained active throughout treatment. Various ECT dosing parameters were attempted, varying pulse width and frequency. Although ECT induced mild transient encephalographic (EEG) changes following ECT stimulations, it was unable to terminate SE. Discussion: This case describes various treatment strategies, constraints, and device limitations when using ECT for the treatment of SE. With wide variability in efficacy rates of ECT in the treatment of SE in the literature, successful and unsuccessful cases offer information on optimizing ECT total charge dose and parameters that yielded success. This case demonstrates an instance of ECT inefficacy in the treatment of SRSE. Here, we discuss the rationale behind the various ECT settings that were selected, and constraints arising from the antiepileptic burden, VNS, and intrinsic limitations of the ECT device itself.

The novel vasopressin receptor (V1aR) antagonist SRX246 reduces anxiety in an experimental model in humans: a randomized proof-of-concept study.

RATIONALE: Arginine vasopressin (AVP) is a neuropeptide that modulates both physiological and emotional responses to threat. Until recently, drugs that target vasopressin receptors (V1a) in the human central nervous system were unavailable. The development of a novel V1a receptor antagonist, SRX246, permits the experimental validation of vasopressin's role in the regulation of anxiety and fear in humans. OBJECTIVES: Here, we examined the effects of SRX246 in a proof-of-concept translational paradigm of fear (phasic response to imminent threat) and anxiety (prolonged response to potential threat). METHODS: Healthy volunteers received both SRX246 and placebo in a randomized, double-blind, counter-balanced order separated by a 5-7-day wash-out period. Threat consisted of unpleasant electric shocks. The "NPU" threat test probed startle reactivity during predictable threat (i.e., fear-potentiated startle) and unpredictable threat (i.e., anxiety-potentiated startle). RESULTS: As predicted, SRX246 decreased anxiety-potentiated startle independent of fear-potentiated startle. CONCLUSIONS: As anxiety-potentiated startle is elevated in anxiety and trauma-associated disorders and decreased by traditional anxiolytics such as SSRIs and benzodiazepines, the V1a receptor is a promising novel treatment target.

A generalized workflow for conducting electric field-optimized, fMRI-guided, transcranial magnetic stimulation.

Transcranial magnetic stimulation (TMS) is a noninvasive method to stimulate the cerebral cortex that has applications in psychiatry, such as in the treatment of depression and anxiety. Although many TMS targeting methods that use figure-8 coils exist, many do not account for individual differences in anatomy or are not generalizable across target sites. This protocol combines functional magnetic resonance imaging (fMRI) and iterative electric-field (E-field) modeling in a generalized approach to subject-specific TMS targeting that is capable of optimizing the stimulation site and TMS coil orientation. To apply this protocol, the user should (i) operationally define a region of interest (ROI), (ii) generate the head model from the structural MRI data, (iii) preprocess the functional MRI data, (iv) identify the single-subject stimulation site within the ROI, and (iv) conduct E-field modeling to identify the optimal coil orientation. In comparison with standard targeting methods, this approach demonstrates (i) reduced variability in the stimulation site across subjects, (ii) reduced scalp-to-cortical-target distance, and (iii) reduced variability in optimal coil orientation. Execution of this protocol requires intermediate-level skills in structural and functional MRI processing. This protocol takes ~24 h to complete and demonstrates how constrained fMRI targeting combined with iterative E-field modeling can be used as a general method to optimize both the TMS coil site and its orientation.

Low-frequency parietal repetitive transcranial magnetic stimulation reduces fear and anxiety.

Anxiety disorders are the most prevalent mental disorders, with few effective neuropharmacological treatments, making treatments development critical. While noninvasive neuromodulation can successfully treat depression, few treatment targets have been identified specifically for anxiety disorders. Previously, we showed that shock threat increases excitability and connectivity of the intraparietal sulcus (IPS). Here we tested the hypothesis that inhibitory repetitive transcranial magnetic stimulation (rTMS) targeting this region would reduce induced anxiety. Subjects were exposed to neutral, predictable, and unpredictable shock threat, while receiving double-blinded, 1 Hz active or sham IPS rTMS. We used global brain connectivity and electric-field modelling to define the single-subject targets. We assessed subjective anxiety with online ratings and physiological arousal with the startle reflex. Startle stimuli (103 dB white noise) probed fear and anxiety during the predictable (fear-potentiated startle, FPS) and unpredictable (anxiety-potentiated startle, APS) conditions. Active rTMS reduced both FPS and APS relative to both the sham and no stimulation conditions. However, the online anxiety ratings showed no difference between the stimulation conditions. These results were not dependent on the laterality of the stimulation, or the subjects' perception of the stimulation (i.e. active vs. sham). Results suggest that reducing IPS excitability during shock threat is sufficient to reduce physiological arousal related to both fear and anxiety, and are consistent with our previous research showing hyperexcitability in this region during threat. By extension, these results suggest that 1 Hz parietal stimulation may be an effective treatment for clinical anxiety, warranting future work in anxiety patients.

Mechanistic link between right prefrontal cortical activity and anxious arousal revealed using transcranial magnetic stimulation in healthy subjects.

Much of the mechanistic research on anxiety focuses on subcortical structures such as the amygdala; however, less is known about the distributed cortical circuit that also contributes to anxiety expression. One way to learn about this circuit is to probe candidate regions using transcranial magnetic stimulation (TMS). In this study, we tested the involvement of the dorsolateral prefrontal cortex (dlPFC), in anxiety expression using 10 Hz repetitive TMS (rTMS). In a within-subject, crossover experiment, the study measured anxiety in healthy subjects before and after a session of 10 Hz rTMS to the right dorsolateral prefrontal cortex (dlPFC). It used threat of predictable and unpredictable shock to induce anxiety and anxiety potentiated startle to assess anxiety. Counter to our hypotheses, results showed an increase in anxiety-potentiated startle following active but not sham rTMS. These results suggest a mechanistic link between right dlPFC activity and physiological anxiety expression. This result supports current models of prefrontal asymmetry in affect, and lays the groundwork for further exploration into the cortical mechanisms mediating anxiety, which may lead to novel anxiety treatments.