Oxidative Stress and Mitochondrial Injury in Chronic Multisymptom Conditions: From Gulf War Illness to Autism Spectrum Disorder

Background: Overlapping chronic multisymptom illnesses (CMI) include Chronic Fatigue Syndrome (CFS), fibromyalgia, irritable bowel syndrome, multiple chemical sensitivity, and Gulf War illness (GWI), and subsets of autism spectrum disorder (ASD). GWI entails a more circumscribed set of experiences that may provide insights of relevance to overlapping conditions.
Objectives: To consolidate evidence regarding a role for oxidative stress and mitochondrial dysfunction (OSMD), as primary mediators in CMI, using GWI as a departure point.
Methods: Exposure relations, character, timecourse and multiplicity of symptoms, and objective correlates of GWI are compared to expectation for OSMD. Objective correlates of OSMD in GWI and overlapping conditions are examined. 
Discussion: OSMD is an expected consequence of known GWI exposures; is compatible with symptom characteristics observed; and accords with objective markers and health conditions linked to GWI, extending to autoimmune disease and infection. Emergent triangulating evidence directly supports OSMD in multisymptom “overlap” CMI conditions, with similarities to, and diagnosed at elevated rates in, GWI, suggesting a common role in each. 
Conclusions: GWI is compatible with a paradigm by which uncompensated exposure to oxidative/nitrative stressors accompanies and triggers mitochondrial dysfunction, cell energy compromise, and multiple downstream effects such as vulnerability to autoantibodies. This promotes a profile of protean symptoms with variable latency emphasizing but not confined to energy-demanding post-mitotic tissues, according with (and accounting for) known properties of multisystem overlap conditions. This advances understanding of GWI; health conditions attending GWI at elevated rates; and overlap conditions like CFS and ASD, providing prospects for vulnerability assessment, mitigation of progression, treatment, and future prevention – with implications germane to additive and excessive environmental oxidative stressor exposures in the civilian setting.
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Alexithymia and apathy in Parkinson's disease: neurocognitive correlates

Non-motor symptoms such as neuropsychiatric and cognitive dysfunction have been found to be common in Parkinson’s disease (PD) but the relation between such symptoms is poorly understood. We focused on alexithymia, an impairment of affective and cognitive emotional processing, as there is evidence for its interaction with cognition in other disorders. Twenty-two non-demented PD patients and 22 matched normal control adults (NC) were administered rating scales assessing neuropsychiatric status, including alexithymia, apathy, and depression, and a series of neuropsychological tests. As expected, PD patients showed more alexithymia than NC, and there was a significant association between alexithymia and disease stage. Alexithymia was associated with performance on non-verbally mediated measures of executive and visuospatial function, but not on verbally mediated tasks. By contrast, there was no correlation between cognition and ratings of either depression or apathy. Our findings demonstrate a distinct association of alexithymia with non-verbal cognition in PD, implicating right hemisphere processes, and differentiate between alexithymia and other neuropsychiatric symptoms in regard to PD cognition.Published versio

Generalized barker sequences

Correlation functions for binary digital systems - binary code and vector analysi

Mood, Personality, and Behavior Changes During Treatment with Statins: A Case Series.

Psychiatric adverse drug reactions (ADRs) have been reported with statin use, but the literature regarding statin-associated mood/behavioral changes remains limited. We sought to elicit information germane to natural history and characteristics of central nervous system/behavioral changes in apparent connection with statin and/or cholesterol-lowering drug use, and delineate mechanisms that may bear on an association. Participants (and/or proxies) self-referred with behavioral and/or mood changes in apparent association with statins completed a survey eliciting cholesterol-lowering drug history, character and impact of behavioral/mood effect, time-course of onset and recovery in relation to drug use/modification, co-occurrence of recognized statin-associated ADRs, and factors relevant to ADR causality determination. Naranjo presumptive ADR causality criteria were assessed. Participants (n = 12) reported mood/behavior change that commenced following statin initiation and persisted or progressed with continued use. Reported problems included violent ideation, irritability, depression, and suicide. Problems resolved with drug discontinuation and recurred with rechallenge where attempted. Eight met presumptive criteria for "probable" or "definite" causality; others had additional factors not considered in Naranjo criteria that bear on casual likelihood. (1) Simvastatin 80 mg was followed in 5 days by irritability/depression culminating in suicide in a man in his 40s (Naranjo criteria: possible causality). (2) Simvastatin 10 mg was followed within 2 weeks by depression in a woman in her 50s (probable causality). (3) Atorvastatin 20 mg was followed in ~1 month by depression and irritability/aggression in a male in his 50s (probable causality). (4) Atorvastatin 10 mg was followed in several months by aggression/irritability and depression culminating in suicide in a man in his 40s (possible causality). (5) Fenofibrate + rosuvastatin (unknown dose), later combined with atorvastatin were followed in 1 month by aggression/irritability in a male in his 30s (probable causality). (6) Lovastatin (unknown dose and time-course to reaction) was followed by depression, dyscontrol of bipolar disorder, and suicide attempts in a male in his 40s (possible causality). (7) Atorvastatin 20 mg was followed within 2 weeks by cognitive compromise, and nightmares, depression, and anxiety culminating in suicide in a man in his teens (definite causality). (8) Simvastatin 10 mg was followed (time-course not recalled) by depression, aggression/irritability culminating in suicide in a man in his 60s (possible causality). (9) Simvastatin 20 mg then atorvastatin 10 mg were followed (time-course not provided) by irritability/aggression in a man in his 60s (definite causality). (10) Atorvastatin 10 then 20 then 40 mg were followed shortly after the dose increase by violent ideation and anxiety in a man in his 30s (probable causality). (11) Atorvastatin 20 mg and then simvastatin 20 mg were followed in 2 weeks by aggression/irritability in a man in his 50s (definite causality). (12) Lovastatin, rosuvastatin, atorvastatin, and simvastatin at varying doses were followed as quickly as 1 day by aggression, irritability, and violent ideation in a man in his 40s (definite causality). Most had risk factors for statin ADRs, and co-occurrence of other, recognized statin ADRs. ADRs had implications for marriages, careers, and safety of self and others. These observations support the potential for adverse mood and behavioral change in some individuals with statin use, extend the limited literature on such effects, and provide impetus for further investigation into these presumptive ADRs. Potential mechanisms are reviewed, including hypothesized mechanisms related to oxidative stress and bioenergetics

The impact of motor symptoms on self-reported anxiety in Parkinson's disease

OBJECTIVE: Anxiety is commonly endorsed in Parkinson's disease (PD) and significantly affects quality of life. The Beck Anxiety Inventory (BAI) is often used but contains items that overlap with common PD motor symptoms (e.g., “hands trembling”). Because of these overlapping items, we hypothesized that PD motor symptoms would significantly affect BAI scores. METHODS: One hundred non-demented individuals with PD and 74 healthy control participants completed the BAI. PD motor symptoms were assessed by the Unified Parkinson's Disease Rating Scale (UPDRS). Factor analysis of the BAI assessed for a PD motor factor, and further analyses assessed how this factor affected BAI scores. RESULTS: BAI scores were significantly higher for PD than NC. A five-item PD motor factor correlated with UPDRS observer-rated motor severity and mediated the PD-control difference on BAI total scores. An interaction occurred, whereby removal of the PD motor factor resulted in a significant reduction in BAI scores for PD relative to NC. The correlation between the BAI and UPDRS significantly declined when controlling for the PD motor factor. CONCLUSIONS: The results indicate that commonly endorsed BAI items may reflect motor symptoms such as tremor instead of, or in addition to, genuine mood symptoms. These findings highlight the importance of considering motor symptoms in the assessment of anxiety in PD and point to the need for selecting anxiety measures that are less subject to contamination by the motor effects of movement disorders.Published versio

Collective behavior of heterogeneous neural networks

We investigate a network of integrate-and-fire neurons characterized by a distribution of spiking frequencies. Upon increasing the coupling strength, the model exhibits a transition from an asynchronous regime to a nontrivial collective behavior. At variance with the Kuramoto model, (i) the macroscopic dynamics is irregular even in the thermodynamic limit, and (ii) the microscopic (single-neuron) evolution is linearly stable.Comment: 4 pages, 5 figure

Dysregulation of visual motion inhibition in major depression

Individuals with depression show depleted concentrations of the inhibitory neurotransmitter GABA in occipital (visual) cortex, predicting weakened inhibition within their visual systems. Yet, visual inhibition in depression remains largely unexplored. To fill this gap, we examined the inhibitory process of centersurround suppression (CSS) of visual motion in depressed individuals. Perceptual performance in discriminating the direction of motion was measured as a function of stimulus presentation time and contrast in depressed individuals (n¼27) and controls (n¼22). CSS was operationalized as the accuracy difference between conditions using large (7.5°) and small (1.5°) grating stimuli. Both depressed and control participants displayed the expected advantage in accuracy for small stimuli at high contrast. A significant interaction emerged between subject group, contrast level and presentation time, indicating that alterations of CSS in depression were modulated by stimulus conditions. At high contrast, depressed individuals showed significantly greater CSS than controls at the 66 ms presentation time (where the effect peaked in both groups). The results' specificity and dependence on stimulus features such as contrast, size and presentation time suggest that they arise from changes in early visual processing, and are not the results of a generalized deficit or cognitive bias.Accepted versio

Risk marker associations with venous thrombotic events: a cross-sectional analysis.

ObjectiveTo examine the interrelations among, and risk marker associations for, superficial and deep venous events-superficial venous thrombosis (SVT), deep venous thrombosis (DVT) and pulmonary embolism (PE).DesignCross-sectional analysis.SettingSan Diego, California, USA.Participants2404 men and women aged 40-79 years from four ethnic groups: non-Hispanic White, Hispanic, African-American and Asian. The study sample was drawn from current and former staff and employees of the University of California, San Diego and their spouses/significant others.Outcome measuresSuperficial and deep venous events, specifically SVT, DVT, PE and combined deep venous events (DVE) comprising DVT and PE.ResultsSignificant correlates on multivariable analysis were, for SVT: female sex, ethnicity (African-American=protective), lower educational attainment, immobility and family history of varicose veins. For DVT and DVE, significant correlates included: heavy smoking, immobility and family history of DVEs (borderline for DVE). For PE, significant predictors included immobility and, in contrast to DVT, blood pressure (BP, systolic or diastolic). In women, oestrogen use duration for hormone replacement therapy, in all and among oestrogen users, predicted PE and DVE, respectively.ConclusionsThese findings fortify evidence for known risk correlates/predictors for venous disease, such as family history, hormone use and immobility. New risk associations are shown. Striking among these is an association of PE, but not DVT, to elevated BP: we conjecture PE may serve as cause rather than consequence. Future studies should evaluate the temporal direction of this association. Oxidative stress and cell energy compromise are proposed to explain and predict many risk factors, operating through cell-death mediated triggering of coagulation activation

Cognitive-behavioral therapy for anxiety in Parkinson's disease

Parkinson's disease (PD) is characterized by motor symptoms, but nonmotor symptoms also significantly impair daily functioning and reduce quality of life. Anxiety is prevalent and debilitating in PD, but remains understudied and undertreated. Much affective research in PD focuses on depression rather than anxiety, and as such, there are no evidence-based treatments for anxiety in this population. Cognitive-behavioral therapy (CBT) has shown promise for treating depression in PD and may be efficacious for anxiety. This exploratory study implemented a multiple-baseline single-case experimental design to evaluate the utility and feasibility of CBT for individuals with PD who also met criteria for a DSM-5 anxiety disorder ( n = 9). Participants were randomized to a 2-, 4-, or 6-week baseline phase, followed by 12 CBT sessions, and two post treatment assessments (immediately post treatment and 6-week follow-up). Multiple outcome measures of anxiety and depression were administered weekly during baseline and intervention. Weekly CBT sessions were conducted in-person ( n = 5) or via secure videoconferencing ( n = 4). At post treatment, seven of the nine participants showed significant reductions in anxiety and/or depression, with changes functionally related to treatment and most improvements maintained at 6-week follow-up. Effects of CBT on secondary outcomes varied across participants, with preliminary evidence for reduction in fear of falling. Adherence and retention were high, as were treatment satisfaction and acceptability. The findings of this pilot study provide preliminary evidence for the utility of CBT as a feasible treatment for anxiety and comorbid depressive symptoms in PD and highlight the potential of telehealth interventions for mood in this population.Accepted manuscrip

Effect of visual cues on the resolution of perceptual ambiguity in Parkinson’s disease and normal aging

Parkinson's disease (PD) and normal aging have been associated with changes in visual perception, including reliance on external cues to guide behavior. This raises the question of the extent to which these groups use visual cues when disambiguating information. Twenty-seven individuals with PD, 23 normal control adults (NC), and 20 younger adults (YA) were presented a Necker cube in which one face was highlighted by thickening the lines defining the face. The hypothesis was that the visual cues would help PD and NC to exert better control over bistable perception. There were three conditions, including passive viewing and two volitional-control conditions (hold one percept in front; and switch: speed up the alternation between the two). In the Hold condition, the cue was either consistent or inconsistent with task instructions. Mean dominance durations (time spent on each percept) under passive viewing were comparable in PD and NC, and shorter in YA. PD and YA increased dominance durations in the Hold cue-consistent condition relative to NC, meaning that appropriate cues helped PD but not NC hold one perceptual interpretation. By contrast, in the Switch condition, NC and YA decreased dominance durations relative to PD, meaning that the use of cues helped NC but not PD in expediting the switch between percepts. Provision of low-level cues has effects on volitional control in PD that are different from in normal aging, and only under task-specific conditions does the use of such cues facilitate the resolution of perceptual ambiguity.Published versio