"When Will All of This End?": A 65-Year-Old Man With Amyotrophic Lateral Sclerosis and Psychiatric Distress.

Patients with amyotrophic lateral sclerosis (ALS) are impacted both physically and psychiatrically during their illness. Emotional distress (ie, anxiety, depression, stress) is common in patients diagnosed with ALS, as prognosis is poor and there are very few effective treatments. The progression of symptoms is unpredictable, and all cases are terminal. Neuropsychiatric symptoms are also increasingly recognized as part of ALS symptomatology. There are currently no empirically supported interventions or best practices for adjustment to ALS. This case presents both the psychological and pharmacologic aspects of caring for a patient with ALS. Psychotherapy utilized a cognitive behavioral therapy-informed approach, and pharmacotherapy was tailored to the specific needs of the patient. We explore how these approaches impacted our patient, as well as how ALS-specific challenges presented throughout the course of treatment.

Treatment of Overthinking: A Multidisciplinary Approach to Rumination and Obsession Spectrum.

Classic psychiatry patients are rare; real-world patients tend to have overlapping features of multiple disorders. Striving for diagnostic certainty, and treatments aimed at tentative diagnoses, often fail these patients. In such cases, tolerating diagnostic ambiguity and "treating the symptoms" can sometimes be transformative. An important symptom, often undertreated in a diagnosis-based approach, is rumination. We present a case study of a woman who, after 20 years of treatment failure, achieved significant symptom relief when her primary complaint-"labored thinking"-was targeted specifically. However, because no seriously ill person has only 1 symptom, 6 clinicians from different subdisciplines will discuss the patient's other issues, ones that an overfocus on rumination might leave out.

Psychotherapy for Functional Neurological (Conversion) Disorder: A Case Bridging Mind, Brain, and Body.

Functional neurologic (conversion) disorder (FND) is a core neuropsychiatric condition directly at the intersection of psychiatry and neurology. Over the past several decades, renewed interest in FND has been catalyzed by use of a "rule-in" diagnostic approach leveraging positive clinical signs specific for the diagnosis. In parallel, advances have occurred in identifying mechanisms, etiologic factors, and evidence-based treatments for this population. While "one size fits all" formulations of the "conversion" of psychological distress into physical symptoms are no longer widely accepted, emotion processing and related psychological constructs (eg, alexithymia, dissociation, threat avoidance) remain central to the conceptual understanding of FND. Furthermore, the biopsychosocial model (foundational to psychiatry) is the prevailing model through which to guide longitudinal treatment, with psychotherapy as an emerging first line intervention for FND. Nonetheless, there is a striking dearth of psychotherapists and mental health providers more broadly that feel well versed in the clinical assessment and management of patients with FND. In this article, we seek to address this gap by presenting the psychotherapy treatment narrative of a woman experiencing paroxysmal functional speech and gait disorder symptoms who had a positive clinical outcome. Our goal with this case presentation and related discussion is to increase the proficiency of psychotherapists in providing treatment to patients with FND.

Cautionary notes on diagnosing functional neurologic disorder as a neurologist-in-training.

Functional neurologic disorder (FND), although neglected for much of the 20th century, is among the most common conditions encountered by neurologists across clinical settings. High prevalence rates and limited provider expertise in FND have created a considerable need to develop educational initiatives and practical suggestions to guide neurologists in training working with this population. To help avoid diagnostic errors, trainees should keep in mind that (1) marginally positive functional examination signs have low specificity; (2) FND can coexist with other neurologic comorbidities; and (3) bizarre, not previously encountered, neurologic presentations should not be mistakenly diagnosed as FND. Furthermore, trainees should be encouraged to longitudinally follow in their clinics a subset of patients with FND to develop the interview, diagnostic, and neuropsychiatric skills needed to effectively care for this population. As the landscape of neurologic care evolves, neurologists with expertise in FND should advise on shaping elements of the educational curriculum for neurology residents.

Intermittent subthalamic nucleus deep brain stimulation induces risk-aversive behavior in human subjects.

The subthalamic nucleus (STN) is a small almond-shaped subcortical structure classically known for its role in motor inhibition through the indirect pathway within the basal ganglia. Little is known about the role of the STN in mediating cognitive functions in humans. Here, we explore the role of the STN in human subjects making decisions under conditions of uncertainty using single-neuron recordings and intermittent deep brain stimulation (DBS) during a financial decision-making task. Intraoperative single-neuronal data from the STN reveals that on high-uncertainty trials, spiking activity encodes the upcoming decision within a brief (500 ms) temporal window during the choice period, prior to the manifestation of the choice. Application of intermittent DBS selectively prior to the choice period alters decisions and biases subject behavior towards conservative wagers.

It is Electric! Electroconvulsive Therapy for Refractory Central Pain and Comorbid Psychiatric Disease.

Central pain syndromes are a complex, diverse group of clinical conditions that are poorly understood. We present a patient with progressive, debilitating central pain and co-existing mood disorders that was refractory to multimodal pharmacologic and nonpharmacologic therapies, but that ultimately responded to electroconvulsive therapy (ECT). The patient described it at various times as her skin being "lit on fire," "stabbed," "squeezed like a boa constrictor," or itching unbearably. She underwent a course of three sequential ECT treatments during her hospitalization and it dramatically decreased her pain. She began maintenance ECT, and a rate of roughly one treatment a month provided persistent pain suppression. Despite this lack of evidence, ECT has a favorable safety profile and can be considered in the therapeutic armamentarium for patients who have exhausted standard treatment regimens who continue to have suffering in the setting of central pain syndromes and coexisting mood disorders.

Long-term follow-up of a randomized AAV2-GAD gene therapy trial for Parkinson's disease.

BACKGROUND. We report the 12-month clinical and imaging data on the effects of bilateral delivery of the glutamic acid decarboxylase gene into the subthalamic nuclei (STN) of advanced Parkinson's disease (PD) patients. METHODS. 45 PD patients were enrolled in a 6-month double-blind randomized trial of bilateral AAV2-GAD delivery into the STN compared with sham surgery and were followed for 12 months in open-label fashion. Subjects were assessed with clinical outcome measures and 18F-fluorodeoxyglucose (FDG) PET imaging. RESULTS. Improvements under the blind in Unified Parkinson's Disease Rating Scale (UPDRS) motor scores in the AAV2-GAD group compared with the sham group continued at 12 months [time effect: F(4,138) = 11.55, P < 0.001; group effect: F(1,35) = 5.45, P < 0.03; repeated-measures ANOVA (RMANOVA)]. Daily duration of levodopa-induced dyskinesias significantly declined at 12 months in the AAV2-GAD group (P = 0.03; post-hoc Bonferroni test), while the sham group was unchanged. Analysis of all FDG PET images over 12 months revealed significant metabolic declines (P < 0.001; statistical parametric mapping RMANOVA) in the thalamus, striatum, and prefrontal, anterior cingulate, and orbitofrontal cortices in the AAV2-GAD group compared with the sham group. Across all time points, changes in regional metabolism differed for the two groups in all areas, with significant declines only in the AAV2-GAD group (P < 0.005; post-hoc Bonferroni tests). Furthermore, baseline metabolism in the prefrontal cortex (PFC) correlated with changes in motor UPDRS scores; the higher the baseline PFC metabolism, the better the clinical outcome. CONCLUSION. These findings show that clinical benefits after gene therapy with STN AAV2-GAD in PD patients persist at 12 months. TRIAL REGISTRATION. ClinicalTrials.gov NCT00643890. FUNDING. Neurologix Inc.

Preliminary Predictors of Initial Attendance, Symptom Burden, and Motor Subtype in a US Functional Neurological Disorders Clinic Population.

BACKGROUND AND OBJECTIVE: Although many patients present with functional neurological symptoms (FNS), few US clinics offer specialized FNS care, and data on clinic attendees remain limited. We determined predictors of initial attendance, symptom burden, and FNS subtype in the first patients referred to our Functional Neurological Disorders Clinic for suspected FNS. METHODS: We reviewed the charts of 62 consecutive patients (46 women, 16 men). Regression analyses investigated predictors of keeping the first scheduled clinic appointment. For the 49 patients who did keep that appointment, regression analyses examined neuropsychiatric factors associated with symptom burden and motor FNS subtypes. RESULTS: The odds of not keeping the first appointment were 10.4 times greater for patients referred from the emergency department than from other sources. The patients who kept their appointment reported a symptom burden that was significantly associated with a past FNS-related emergency department visit and a diagnosis of another medically unexplained somatic syndrome. The number of FNS findings on neurological examination also correlated with a history of an FNS-related emergency department visit. Patients with psychogenic non-epileptic seizures reported cognitive complaints and prior psychiatric hospitalizations significantly more often than did patients with other FNS. One fourth of all patients had two or more motor FNS. CONCLUSIONS: In our FNS cohort, patients were less likely to keep an initial clinic appointment if they were referred from the emergency department than from other sources. Patients with psychogenic non-epileptic seizures were more likely to report cognitive symptoms and past psychiatric hospitalizations than patients with other FNS.

Association between α-synuclein blood transcripts and early, neuroimaging-supported Parkinson's disease.

There are no cures for neurodegenerative diseases and this is partially due to the difficulty of monitoring pathogenic molecules in patients during life. The Parkinson's disease gene α-synuclein (SNCA) is selectively expressed in blood cells and neurons. Here we show that SNCA transcripts in circulating blood cells are paradoxically reduced in early stage, untreated and dopamine transporter neuroimaging-supported Parkinson's disease in three independent regional, national, and international populations representing 500 cases and 363 controls and on three analogue and digital platforms with P < 0.0001 in meta-analysis. Individuals with SNCA transcripts in the lowest quartile of counts had an odds ratio for Parkinson's disease of 2.45 compared to individuals in the highest quartile. Disease-relevant transcript isoforms were low even near disease onset. Importantly, low SNCA transcript abundance predicted cognitive decline in patients with Parkinson's disease during up to 5 years of longitudinal follow-up. This study reveals a consistent association of reduced SNCA transcripts in accessible peripheral blood and early-stage Parkinson's disease in 863 participants and suggests a clinical role as potential predictor of cognitive decline. Moreover, the three independent biobank cohorts provide a generally useful platform for rapidly validating any biological marker of this common disease.

Discovery of AZD3199, An Inhaled Ultralong Acting ß2 Receptor Agonist with Rapid Onset of Action.

A series of dibasic des-hydroxy ß2 receptor agonists has been prepared and evaluated for potential as inhaled ultralong acting bronchodilators. Determination of activities at the human ß-adrenoreceptors demonstrated a series of highly potent and selective ß2 receptor agonists that were progressed to further study in a guinea pig histamine-induced bronchoconstriction model. Following further assessment by onset studies in guinea pig tracheal rings and human bronchial rings contracted with methacholine (guinea pigs) or carbachol (humans), duration of action studies in guinea pigs after intratracheal (i.t.) administration and further selectivity and safety profiling AZD3199 was shown to have an excellent over all profile and was progressed into clinical evaluation as a new ultralong acting inhaled ß2 receptor agonist with rapid onset of action.

Unrecognized vitamin D3 deficiency is common in Parkinson disease: Harvard Biomarker Study.

OBJECTIVE: To conclusively test for a specific association between the biological marker 25-hydroxy-vitamin D3, a transcriptionally active hormone produced in human skin and liver, and the prevalence and severity of Parkinson disease (PD). METHODS: We used liquid chromatography/tandem mass spectrometry to establish an association specifically between deficiency of 25-hydroxy-vitamin D3 and PD in a cross-sectional and longitudinal case-control study of 388 patients (mean Hoehn and Yahr stage of 2.1 ± 0.6) and 283 control subjects free of neurologic disease nested in the Harvard Biomarker Study. RESULTS: Plasma levels of 25-hydroxy-vitamin D3 were associated with PD in both univariate and multivariate analyses with p values = 0.0034 and 0.047, respectively. Total 25-hydroxy-vitamin D levels, the traditional composite measure of endogenous and exogenous vitamin D, were deficient in 17.6% of patients with PD compared with 9.3% of controls. Low 25-hydroxy-vitamin D3 as well as total 25-hydroxy-vitamin D levels were correlated with higher total Unified Parkinson's Disease Rating Scale scores at baseline and during follow-up. CONCLUSIONS: Our study reveals an association between 25-hydroxy-vitamin D3 and PD and suggests that thousands of patients with PD in North America alone may be vitamin D-deficient. This finding has immediate relevance for individual patients at risk of falls as well as public health, and warrants further investigation into the mechanism underlying this association.

Studying task-related activity of individual neurons in the human brain.

Single-neuronal studies remain the gold standard for studying brain function. Here we describe a protocol for studying task-related single-neuronal activity in human subjects during neurosurgical procedures involving microelectrode recordings. This protocol has two phases: a preoperative phase and an intraoperative phase. During the preoperative phase, we discuss informed consent, equipment setup and behavioral testing. During the intraoperative phase, we discuss the procedure for microelectrode recordings. Because patients are often awake during these procedures, this protocol can be performed in conjunction with behavioral tasks for studying a variety of cognitive functions. We describe the protocol in detail and provide two examples of expected results. In addition, we discuss the potential difficulties and pitfalls related to intraoperative studies. This protocol takes ∼1.5 h to complete.

Association of SNCA with Parkinson: replication in the Harvard NeuroDiscovery Center Biomarker Study.

BACKGROUND: Mutations in the α-synuclein gene (SNCA) cause autosomal dominant forms of Parkinson's disease, but the substantial risk conferred by this locus to the common sporadic disease has only recently emerged from genome-wide association studies. METHODS: We genotyped a prioritized noncoding variant in SNCA intron 4 in 344 patients with Parkinson's disease and 275 controls from the longitudinal Harvard NeuroDiscovery Center Biomarker Study. RESULTS: The common minor allele of rs2736990 was associated with elevated disease susceptibility (odds ratio, 1.40; P = .0032). CONCLUSIONS: This result increases confidence in the notion that in many clinically well-characterized patients, genetic variation in SNCA contributes to "sporadic" disease.

Design driven HtL: The discovery and synthesis of new high efficacy ß2-agonists.

The design and synthesis of a new series of high efficacy ß(2)-agonists devoid of the key benzylic alcohol present in previously described highly efficacious ß(2)-agonists is reported. A hypothesis for the unprecedented level of efficacy is proposed based on considerations of ß(2)-adrenoceptor crystal structure, other biophysical data and modeling studies.

Temporary interruption of deep brain stimulation for Parkinson's disease during outpatient electroconvulsive therapy for major depression: a novel treatment strategy.

The safety of electroconvulsive therapy (ECT) in patients with deep brain stimulation (DBS) has not been established. Cases reported had no adverse events, but DBS was withheld throughout the weeks of the ECT course. The authors report the first case of temporary interruption of DBS only during the minutes of each outpatient ECT.

AAV2-GAD gene therapy for advanced Parkinson's disease: a double-blind, sham-surgery controlled, randomised trial.

BACKGROUND: Gene transfer of glutamic acid decarboxylase (GAD) and other methods that modulate production of GABA in the subthalamic nucleus improve basal ganglia function in parkinsonism in animal models. We aimed to assess the effect of bilateral delivery of AAV2-GAD in the subthalamic nucleus compared with sham surgery in patients with advanced Parkinson's disease. METHODS: Patients aged 30-75 years who had progressive levodopa-responsive Parkinson's disease and an overnight off-medication unified Parkinson's disease rating scale (UPDRS) motor score of 25 or more were enrolled into this double-blind, phase 2, randomised controlled trial, which took place at seven centres in the USA between Nov 17, 2008, and May 11, 2010. Infusion failure or catheter tip location beyond a predefined target zone led to exclusion of patients before unmasking for the efficacy analysis. The primary outcome measure was the 6-month change from baseline in double-blind assessment of off-medication UPDRS motor scores. This trial is registered with ClinicalTrials.gov, NCT00643890. FINDINGS: Of 66 patients assessed for eligibility, 23 were randomly assigned to sham surgery and 22 to AAV2-GAD infusions; of those, 21 and 16, respectively, were analysed. At the 6-month endpoint, UPDRS score for the AAV2-GAD group decreased by 8·1 points (SD 1·7, 23·1%; p<0·0001) and by 4·7 points in the sham group (1·5, 12·7%; p=0·003). The AAV2-GAD group showed a significantly greater improvement from baseline in UPDRS scores compared with the sham group over the 6-month course of the study (RMANOVA, p=0·04). One serious adverse event occurred within 6 months of surgery; this case of bowel obstruction occurred in the AAV2-GAD group, was not attributed to treatment or the surgical procedure, and fully resolved. Other adverse events were mild or moderate, likely related to surgery and resolved; the most common were headache (seven patients in the AAV2-GAD group vs two in the sham group) and nausea (six vs two). INTERPRETATION: The efficacy and safety of bilateral infusion of AAV2-GAD in the subthalamic nucleus supports its further development for Parkinson's disease and shows the promise for gene therapy for neurological disorders. FUNDING: Neurologix.

Brain illness and creativity: mechanisms and treatment risks.

Brain diseases and their treatment may help or hurt creativity in ways that shape quality of life. Increased creative drive is associated with bipolar disorder, depression, psychosis, temporal lobe epilepsy, frontotemporal dementia, Parkinson disease treatments, and autism. Creativity depends on goal-driven approach motivation from midbrain dopaminergic systems. Fear-driven avoidance motivation is of less aid to creativity. When serotonin and norepinephrine lower motivation and flexible behaviour, they can inhibit creativity. Hemispheric lateralization and frontotemporal connections must interact to create new ideas and conceptual schemes. The right brain and temporal lobe contribute skill in novelty detection, while the left brain and frontal lobe foster approach motivation and more easily generate new patterns of action from the novel perceptions. Genes and phenotypes that increase plasticity and creativity in tolerant environments with relaxed selection pressure may confer risk in rigorous environments. Few papers substantively address this important but fraught topic. Antidepressants (ADs) that inhibit fear-driven motivation, such as selective serotonin reuptake inhibitors, sometimes inhibit goal-oriented motivation as well. ADs that boost goal-directed motivation, such as bupropion, may remediate this effect. Benzodiazepines and alcohol may be counterproductive. Although dopaminergic agonists sometimes stimulate creativity, their doing so may inappropriately disinhibit behaviour. Dopamine antagonists may suppress creative motivation; lithium and anticonvulsant mood stabilizers may do so less. Physical exercise and REM sleep may help creativity. Art therapy and psychotherapy are not well studied. Preserving creative motivation can help creativity and other aspects of well-being in all patients, not just artists or researchers.

Ventral intermediate thalamic stimulation for monoclonal gammopathy-associated tremor: case report.

BACKGROUND AND IMPORTANCE: Peripheral and central sensory loss are often associated with significant tremor or sensory ataxia, which can be highly refractory to medical therapy. CLINICAL PRESENTATION: We present the case of a 67-year-old man with progressive and debilitating intention tremor from monoclonal gammopathy-associated peripheral neuropathy. The patient was implanted with bilateral thalamic deep brain stimulator electrodes under microelectrode guidance. Following optimization of stimulation parameters, the patient's appendicular tremor and gait improved, as did his general activities of daily living. CONCLUSION: These initial findings suggest that deep brain stimulation may benefit not only tremor presumed to originate from central nervous system dysfunction, but also tremor originating peripherally from neuropathy-related sensory loss.