Impaired flexible reward learning in ADHD patients is associated with blunted reinforcement sensitivity and neural signals in ventral striatum and parietal cortex.

Reward-based learning and decision-making are prime candidates to understand symptoms of attention deficit hyperactivity disorder (ADHD). However, only limited evidence is available regarding the neurocomputational underpinnings of the alterations seen in ADHD. This concerns flexible behavioral adaption in dynamically changing environments, which is challenging for individuals with ADHD. One previous study points to elevated choice switching in adolescent ADHD, which was accompanied by disrupted learning signals in medial prefrontal cortex. Here, we investigated young adults with ADHD (n = 17) as compared to age- and sex-matched controls (n = 17) using a probabilistic reversal learning experiment during functional magnetic resonance imaging (fMRI). The task requires continuous learning to guide flexible behavioral adaptation to changing reward contingencies. To disentangle the neurocomputational underpinnings of the behavioral data, we used reinforcement learning (RL) models, which informed the analysis of fMRI data. ADHD patients performed worse than controls particularly in trials before reversals, i.e., when reward contingencies were stable. This pattern resulted from 'noisy' choice switching regardless of previous feedback. RL modelling showed decreased reinforcement sensitivity and enhanced learning rates for negative feedback in ADHD patients. At the neural level, this was reflected in a diminished representation of choice probability in the left posterior parietal cortex in ADHD. Moreover, modelling showed a marginal reduction of learning about the unchosen option, which was paralleled by a marginal reduction in learning signals incorporating the unchosen option in the left ventral striatum. Taken together, we show that impaired flexible behavior in ADHD is due to excessive choice switching ('hyper-flexibility'), which can be detrimental or beneficial depending on the learning environment. Computationally, this resulted from blunted sensitivity to reinforcement of which we detected neural correlates in the attention-control network, specifically in the parietal cortex. These neurocomputational findings remain preliminary due to the relatively small sample size.

Responsivity of the Striatal Dopamine System to Methylphenidate-A Within-Subject I-123-ß-CIT-SPECT Study in Male Children and Adolescents With Attention-Deficit/Hyperactivity Disorder.

Background: Methylphenidate (MPH) is the first-line pharmacological treatment of attention-deficit/hyperactivity disorder (ADHD). MPH binds to the dopamine (DA) transporter (DAT), which has high density in the striatum. Assessments of the striatal dopamine transporter by single positron emission computed tomography (SPECT) in childhood and adolescent patients are rare but can provide insight on how the effects of MPH affect DAT availability. The aim of our within-subject study was to investigate the effect of MPH on DAT availability and how responsivity to MPH in DAT availability is linked to clinical symptoms and cognitive functioning. Methods: Thirteen adolescent male patients (9-16 years) with a diagnosis of ADHD according to the DSM-IV and long-term stimulant medication (for at least 6 months) with MPH were assessed twice within 7 days using SPECT after application of I-123-ß-CIT to examine DAT binding potential (DAT BP). SPECT measures took place in an on- and off-MPH status balanced for order across participants. A virtual reality continuous performance test was performed at each time point. Further clinical symptoms were assessed for baseline off-MPH. Results: On-MPH status was associated with a highly significant change (-29.9%) of striatal DAT BP as compared to off-MPH (t = -4.12, p = 0.002). A more pronounced change in striatal DAT BP was associated with higher off-MPH attentional and externalizing symptom ratings (Pearson r = 0.68, p = 0.01). Striatal DAT BP off-MPH, but not on-MPH, was associated with higher symptom ratings (Pearson r = 0.56, p = 0.04). Conclusion: Our findings corroborate previous reports from mainly adult samples that MPH changes striatal DAT BP availability and suggest higher off-MPH DAT BP, likely reflecting low baseline DA levels, as a marker of symptom severity.

CNS imaging characteristics in fibromyalgia patients with and without peripheral nerve involvement.

We tested the hypothesis that reduced skin innervation in fibromyalgia syndrome is associated with specific CNS changes. This prospective case-control study included 43 women diagnosed with fibromyalgia syndrome and 40 healthy controls. We further compared the fibromyalgia subgroups with reduced (n = 21) and normal (n = 22) skin innervation. Brains were analysed for cortical volume, for white matter integrity, and for functional connectivity. Compared to controls, cortical thickness was decreased in regions of the frontal, temporal and parietal cortex in the fibromyalgia group as a whole, and decreased in the bilateral pericalcarine cortices in the fibromyalgia subgroup with reduced skin innervation. Diffusion tensor imaging revealed a significant increase in fractional anisotropy in the corona radiata, the corpus callosum, cingulum and fornix in patients with fibromyalgia compared to healthy controls and decreased FA in parts of the internal capsule and thalamic radiation in the subgroup with reduced skin innervation. Using resting-state fMRI, the fibromyalgia group as a whole showed functional hypoconnectivity between the right midfrontal gyrus and the posterior cerebellum and the right crus cerebellum, respectively. The subgroup with reduced skin innervation showed hyperconnectivity between the inferior frontal gyrus, the angular gyrus and the posterior parietal gyrus. Our results suggest that the subgroup of fibromyalgia patients with pronounced pathology in the peripheral nervous system shows alterations in morphology, structural and functional connectivity also at the level of the encephalon. We propose considering these subgroups when conducting clinical trials.

Microsurgical clipping and endovascular treatment of middle cerebral artery aneurysms in an interdisciplinary treatment concept: Comparison of long-term results.

OBJECTIVE: Treatment of middle cerebral artery (MCA) aneurysms has been historically considered as the almost exclusive domain of microsurgical clipping. This retrospective single-center study assesses whether microsurgical clipping or endovascular treatment (i.e. coiling and/or stenting) for MCA aneurysms yielded better occlusion rates and clinical outcome. METHODS: We identified patients with a minimum clinical follow-up of 12 months who had undergone MCA aneurysm repair either by clipping or by endovascular treatment between 2005 and 2015. Aneurysm occlusion rates were assessed by the Raymond-Roy Occlusion Classification (RROC) and patients' clinical outcome was measured by the modified Rankin Scale (mRS). All patients had been treated in an interdisciplinary treatment concept at a large neurovascular center; both treatment modalities were available at all times. RESULTS: Ninety-two eligible patients with MCA aneurysms, of whom 21.7% patients were treated for subarachnoid hemorrhages, were included; 38 patients underwent endovascular therapy and 54 clipping. The median age at treatment was 53.5 years (range, 25-79 years) and the median clinical follow-up was 98.5 months (range, 18-213 months). Occlusion rates were significantly higher in the clipping cohort (RROC = 1: 96.3% vs 78.9%; p = 0.04), long-term clinical outcome was better in the endovascular treatment cohort (mRS ≤ 1: 100.0% vs 90.8%; p < 0.01). Permanent treatment-associated morbidity was seen more commonly in the clipping cohort (9.3% vs 0.0%). CONCLUSIONS: Both treatment modalities are associated with excellent clinical and radiological outcome if applied within an interdisciplinary treatment concept. Endovascular aneurysm repair appears to be an attractive treatment alternative compared to clipping with low complication rates for well-selected patients.