The contribution of [1H] magnetic resonance spectroscopy to the study of excitation-inhibition in autism.

Autism spectrum disorder (ASD) affects over 1:100 of the population and costs the UK more than £32bn and the USA more than $175bn (£104bn) annually. Its core symptoms are social and communication difficulties, repetitive behaviours and sensory hyper- or hypo-sensitivities. A highly diverse phenotypic presentation likely reflects its etiological heterogeneity and makes finding treatment targets for ASD challenging. In addition, there are no means to identify biologically responsive individuals who may benefit from specific interventions. There is hope however, and in this review we consolidate how findings from magnetic resonance spectroscopy (MRS) add to the evidence that differences in the brain's excitatory glutamate and inhibitory γ-aminobutyric acid (GABA) balance may be both a key biomarker and a tractable treatment target in ASD.

UK prescribing practices as proxy markers of unmet need in allergic rhinitis: a retrospective observational study.

Little data on UK prescribing patterns and treatment effectiveness for allergic rhinitis (AR) are available. We quantified unmet pharmacologic needs in AR by assessing AR treatment effectiveness based on the prescribing behaviour of UK general practitioners (GP) during two consecutive pollen seasons (2009 and 2010). We conducted a retrospective observational study with the data from the Optimum Patient Care Research Database. We assessed diagnoses and prescription data for patients with a recorded diagnosis of rhinitis who took rhinitis medication during the study period. We assessed the data from 25,069 patients in 2009 and 22,381 patients in 2010. Monotherapy was the initial prescription of the season for 67% of patients with seasonal AR (SAR) and 77% of patients with nonseasonal upper airways disease (NSUAD), for both years. Initial oral antihistamine (OAH) or intranasal corticosteroid (INS) monotherapy proved insufficient for >20% of SAR and >37% of NSUAD patients. Multiple therapy was the initial prescription for 33% of SAR and 23% of NSUAD in both years, rising to 45% and >50% by season end, respectively. For NSUAD, dual-therapy prescriptions doubled and triple-therapy prescriptions almost tripled during both seasons. Many patients revisited their GP regardless of initial prescription. Initial OAH or INS monotherapy provides insufficient symptom control for many AR patients. GPs often prescribe multiple therapies at the start of the season, with co-prescription becoming more common as the season progresses. However, patients prescribed multiple therapies frequently revisit their GP, presumably to adjust treatment. These data suggest the need for more effective AR treatment and management strategies.

Cortical and subcortical glutathione levels in adults with autism spectrum disorder.

Increased oxidative stress has been postulated to contribute to the pathogenesis of autism spectrum disorder (ASD). However, reports of alterations in oxidation markers including glutathione (GSH), the major endogenous antioxidant, are indirect, coming from blood plasma level measurements and postmortem studies. Therefore we used in-vivo 3 Tesla proton magnetic resonance spectroscopy ([1H]MRS) to directly measure GSH concentrations in the basal ganglia (BG) and the dorsomedial prefrontal cortex of 21 normally intelligent adult males with ASD and 29 controls who did not differ in age or IQ. There was no difference in brain GSH between patients and controls in either brain area; neither did GSH levels correlate with measures of clinical severity in patients. Thus [1H]MRS measures of cortical and subcortical GSH are not a biomarker for ASD in intellectually able adult men.

Neuroligin-2 and the tightrope of excitation/inhibition balance in the prefrontal cortex.

Excitation/inhibition imbalance is implicated in symptoms of neuropsychiatric disorders. We discuss a study by Liang et al. (Mol Psychiatry 20: 850-859, 2015) demonstrating that the conditional knockout of neuroligin-2, a postsynaptic adhesion protein, in the prefrontal cortex of adult mice results in alterations in inhibitory synaptic properties. However, behavioral impairments emerged prior to the development of detectable changes in excitation/inhibition ratio. This suggests there may be network-specific excitation/inhibition ratios, some of which are more vulnerable to disruption than others.

Targeting Glia with N-Acetylcysteine Modulates Brain Glutamate and Behaviors Relevant to Neurodevelopmental Disorders in C57BL/6J Mice.

An imbalance between excitatory (E) glutamate and inhibitory (I) GABA transmission may underlie neurodevelopmental conditions such as autism spectrum disorder (ASD) and schizophrenia. This may be direct, through alterations in synaptic genes, but there is increasing evidence for the importance of indirect modulation of E/I balance through glial mechanisms. Here, we used C57BL/6J mice to test the hypothesis that striatal glutamate levels can be shifted by N-acetylcysteine (NAC), which acts at the cystine-glutamate antiporter of glial cells. Striatal glutamate was quantified in vivo using proton magnetic resonance spectroscopy. The effect of NAC on behaviors relevant to ASD was examined in a separate cohort. NAC induced a time-dependent decrease in striatal glutamate, which recapitulated findings of lower striatal glutamate reported in ASD. NAC-treated animals were significantly less active and more anxious in the open field test; and NAC-treated females had significantly impaired prepulse inhibition of startle response. This at least partly mimics greater anxiety and impaired sensorimotor gating reported in neurodevelopmental disorders. Thus glial mechanisms regulate glutamate acutely and have functional consequences even in adulthood. Glial cells may be a potential drug target for the development of new therapies for neurodevelopmental disorders across the life-span.

Obsessive-compulsive disorder patients have a reduced sense of control on the illusion of control task.

There is disagreement regarding the role of perceived control in obsessive-compulsive disorder (OCD). The present study used a traditional illusion of control paradigm (Alloy and Abramson, 1979) to empirically test control estimation in OCD. Twenty-six OCD patients and 26 matched comparison subjects completed an illusion of control task wherein their goal was to attempt to exert control over a light bulb. The density of reinforcement (high, low) and the valence of trials (gain, loss) were experimentally manipulated within subjects. Unbeknownst to participants, the illumination of the light bulb was predetermined and irrespective of their behavior. OCD patients exhibited lower estimates of control compared with healthy comparison subjects. There were no interactions between group and outcome density or group and valence. We found that OCD patients endorse lower estimates of control than comparison subjects. This finding highlights a potential role for contingency learning in the disorder.