Probabilistic classification learning with corrective feedback is associated with in vivo striatal dopamine release in the ventral striatum,while learning without feedback is not

The basal ganglia (BG) mediate certain types of procedural learning, such as probabilistic classification learning on the ‘weather prediction task’ (WPT). Patients with Parkinson's disease (PD), who have BG dysfunction, are impaired at WPT‐learning, but it remains unclear what component of the WPT is important for learning to occur. We tested the hypothesis that learning through processing of corrective feedback is the essential component and is associated with release of striatal dopamine. We employed two WPT paradigms, either involving learning via processing of corrective feedback (FB) or in a paired associate manner (PA). To test the prediction that learning on the FB but not PA paradigm would be associated with dopamine release in the striatum, we used serial ¹¹C‐raclopride (RAC) positron emission tomography (PET), to investigate striatal dopamine release during FB and PA WPT‐learning in healthy individuals. Two groups, FB, (n = 7) and PA (n = 8), underwent RAC PET twice, once while performing the WPT and once during a control task. Based on a region‐of‐interest approach, striatal RAC‐binding potentials reduced by 13–17% in the right ventral striatum when performing the FB compared to control task, indicating release of synaptic dopamine. In contrast, right ventral striatal RAC binding non‐significantly increased by 9% during the PA task. While differences between the FB and PA versions of the WPT in effort and decision‐making is also relevant, we conclude striatal dopamine is released during FB‐based WPT‐learning, implicating the striatum and its dopamine connections in mediating learning with FB. Hum Brain Mapp 35:5106–5115, 2014. © 2014 The Authors. Human Brain Mapping Published by Wiley Periodicals, Inc.     

Self-reported reasons for discontinuation or continuation of antipsychotic medication in individuals with first-episode schizophrenia

Aim

Many individuals with schizophrenia discontinue initially prescribed antipsychotics. Knowledge on reasons for discontinuation among individuals with first-episode schizophrenia is sparse. We aimed to describe reasons for discontinuation and continuation, differences between individuals discontinuing and continuing, and factors predicting reasons for discontinuation or continuation.

Methods

This was a prospective cohort study with a post hoc design. Individuals with first-episode schizophrenia were included from early intervention teams in Denmark from 2009–2012. Sociodemographic and clinical variables were collected at baseline and reasons for discontinuation and continuation of antipsychotics were assessed at 3.5-year follow-up.

Results

Among 215 patients, 76 reported reasons for discontinuation and 139 for continuation. The most frequent reasons for discontinuation were “side effects” and “patient believed he/she no longer needed the medication because he/she was now better”. The most frequent reasons for continuation were “benefits for positive symptoms” and “another person told them to”. Individuals who discontinued antipsychotics were at baseline younger, had longer DUP, less negative symptoms, better social function, lower compliance, higher self-belief of coping, and fewer used antipsychotics compared to those continuing antipsychotics.

Conclusions

The effect of antipsychotics is the main reason to continue, whereas side effects were the main reason to discontinue. Knowledge of reasons to discontinue or continue is helpful in shared decision-making, identifying individuals with high odds of discontinuation, improving adherence, and helping with safe discontinuation.     

Lyme neuroborreliosis: An unusual case with extensive (peri)vasculitis of the middle cerebral artery

Lyme disease is a tick-borne infection caused by Borrelia burgdorferi sensu latu. Neuroborreliosis is reported in approximately 10% of patients with Lyme disease. We report a patient with central nervous system (CNS) large vessel vasculitis, ischemic stroke, and tumefactive contrast-enhancing brain lesions, an unusual complication of neuroborreliosis. A 56-year-old man presented with headache and disorientation for 1 month. Magnetic resonance imaging revealed basal meningitis with rapidly progressing frontotemporoinsular edema and (peri)vasculitis. Transcranial ultrasound confirmed stenosed medial cerebral arteries. [¹⁸F]GE-180 microglia positron emission tomography (PET) showed frontotemporoinsular signal more pronounced on the right. [¹⁸F]FET amino acid PET demonstrated low tracer uptake, suggesting an inflammatory process. Cerebrospinal fluid (CSF) showed lymphomonocytosis (243/μl), intrathecal anti-Borrelia IgM (CSF/serum index = 15.65, normal < 1.5) and anti-Borrelia IgG (CSF/serum index = 6.5, normal < 1.5), and elevated CXCL13 (29.2 pg/ml, normal < 10 pg/ml). Main differential diagnoses of neurotuberculosis and perivascular CNS lymphoma were ruled out by biopsy and Quantiferon enzyme-linked immunosorbent assay. Ceftriaxone (28 days), cortisone, and nimodipine (3 months) led to full recovery. Neuroborreliosis is an important differential diagnosis in patients with CNS large vessel vasculitis and tumefactive contrast-enhancing brain lesions, mimicking perivascular CNS lymphoma or neurotuberculosis as main neuroradiological differential diagnoses. Vasculopathy and cerebrovascular events are rare in neuroborreliosis but should be considered, especially in endemic areas.     

Levodopa-induced striatal activation in Parkinson's disease: A functional MRI study

ObjectiveTo assess the effect of a single levodopa dose (200 mg levodopa, 50 mg carbidopa = sdLD) on cortical and subcortical motor-circuit activation during bimanual grip force in patients with Parkinson's disease (PD).Patients and methodsWe studied 12 right-handed patients with PD (Hoehn–Yahr stages I–II) after a period of at least 12 h without medication (OFF state) and a second time 1 h after oral administration of sdLD (ON state) using functional magnetic resonance imaging (fMRI). Blood-oxygenation-level-dependency (BOLD) fMRI was measured while participants underwent two unilateral and two bimanual grip force movements with a defined movement amplitude and force (10 N) in a block design. 12 age matched healthy subjects were studied as controls (without administration of sdLD).ResultsBimanual grip force tasks activated a specific pattern of cortical and subcortical structures in all patients during the OFF state and after levodopa administration with statistically significant differences in putamen and thalamus comparing the OFF and ON condition. In contrast, no such significant changes were observed in cortical structures. Between-group analysis revealed higher putaminal activity in controls compared to OFF state in bimanual tasks, while these differences disappeared after administration of levodopa.ConclusionsOur results indicate that the putamen and thalamus are the regions within the cortico-subcortical motor-circuit with most prominent response to levodopa. In our study, cortical motor areas did not respond to levodopa as one could have expected from previous studies. These findings contribute to the increasing evidence that an extended model of the underlying pathophysiology of motor dysfunctions in PD is warranted.     

Alzheimer disease macrophages shuttle amyloid-beta from neurons to vessels, contributing to amyloid angiopathy

Neuronal accumulation of oligomeric amyloid-β (Αβ) is considered the proximal cause of neuronal demise in Alzheimer disease (AD) patients. Blood-borne macrophages might reduce Aβ stress to neurons by immigration into the brain and phagocytosis of Αβ. We tested migration and export across a blood-brain barrier model, and phagocytosis and clearance of Αβ by AD and normal subjects’ macrophages. Both AD and normal macrophages were inhibited in Αβ export across the blood-brain barrier due to adherence of Aβ-engorged macrophages to the endothelial layer. In comparison to normal subjects’ macrophages, AD macrophages ingested and cleared less Αβ, and underwent apoptosis upon exposure to soluble, protofibrillar, or fibrillar Αβ. Confocal microscopy of stained AD brain sections revealed oligomeric Aβ in neurons and apoptotic macrophages, which surrounded and infiltrated congophilic microvessels, and fibrillar Aβ in plaques and microvessel walls. After incubation with AD brain sections, normal subjects’ monocytes intruded into neurons and uploaded oligomeric Aβ. In conclusion, in patients with AD, macrophages appear to shuttle Aβ from neurons to vessels where their apoptosis may release fibrillar Aβ, contributing to cerebral amyloid angiopathy. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users. J. Zaghi and B. Goldenson contributed equally.     

Methylation and QTDT analysis of the 5-HT2A receptor 102C allele: analysis of suicidality in major psychosis

Suicide is an act deliberately initiated and performed by a person with full knowledge that a fatal outcome is probable. The serotonin 2A (5-HT2A) receptor gene has been implicated in the pathogenesis of suicidal behaviour by a genetic association between the 5-HT2A T102C silent polymorphism and suicidality in patients with mood disorders and schizophrenia. However, a recent meta-analysis failed to confirm this association. We developed an improved quantitative assay for the measurement of allele-specific methylation of the 5-HT2A gene, and found that the methylation of the C allele in the pre-frontal cortex of heterozygous suicide victims (n = 10) was not significantly different in comparison with the non-suicide group (n = 10) (p = 0.084). We also analyzed methylation of the C allele in white blood cell DNA from bipolar and schizophrenic attempters and found a significant difference in the schizophrenic attempters (p = 0.00013) but not in the bipolar attempters (p = 0.616).Because the 5-HT2A gene is subject to imprinting, the parent-of-origin may affect inheritance of suicidal behaviour. Thus, we examined the parental origin of specific alleles for genetic association in a genetic family-based sample of major psychoses in which information on suicidal behaviour was available. This result suggests that methylation of the 102C allele does not influence completed suicide.     

Subjective and objective measures of sleep in children with attention-deficit/hyperactivity disorder

ObjectiveTo compare objective and subjective measures of sleep in children with attention-deficit/hyperactivity disorder (ADHD) and healthy control subjects.MethodsIncluded were 107 unmedicated children with ADHD and 46 healthy control subjects, all aged 6–14. Sleep–wake patterns were monitored with actigraphy for at least five consecutive days. Subjects and parents completed daily electronic diaries assessing sleep and daytime behavior.ResultsActigraphy data from 80 ADHD patients and 45 control subjects showed that, compared to the healthy control group, the ADHD group experienced shorter actual sleep time (defined as time in minutes [from sleep onset to final morning awakening] of all epochs scored as sleep [i.e., excluding total duration of all epochs scored as “wake”]) (489.39 vs. 460.30 min, p = .001), significantly fewer sleep interruptions (44.45 vs. 35.33, p < .001), but more total interrupted sleep time (44.49 vs. 56.70 min, p = .002). Child diaries indicated children with ADHD had significantly more daytime sleepiness and difficulty getting up and less refreshing sleep. Parent diaries indicated children with ADHD had significantly more behavioral difficulties than the control group.ConclusionsResults suggest children with ADHD have reduced sleep quantity and more disturbed sleep on actigraphic measures, reduced sleep quality on the self report, and more problematic behaviors on the parent report. Clinical interventions for children with ADHD who present with sleep problems should include screening for etiologic and exacerbating factors, institution of behavioral-management strategies, and consideration of pharmacologic treatment targeted toward evening ADHD symptoms.     

The incidence of cerebrospinal fluid leak after vestibular schwannoma surgery.

OBJECTIVE: To review the incidence of cerebrospinal fluid leak after vestibular schwannoma removal reported in the literature. DATA SOURCES: MEDLINE and PubMed literature search using the terms "acoustic neuroma" or "vestibular schwannoma," and "cerebrospinal fluid leak" or "cerebrospinal fluid fistula" covering the period from 1985 to the present in the English language literature. A review of bibliographies of these studies was also performed. STUDY SELECTION: Criteria for inclusion in this meta-analysis consisted of the availability of extractable data from studies presenting a defined group of patients who had undergone primary vestibular schwannoma removal and for whom the presence and absence of cerebrospinal fluid leakage was reported. Studies reporting combined approaches were excluded. No duplications of patient populations were included. Twenty-five studies met the inclusion criteria. DATA EXTRACTION: Quality of the studies was determined by the design of each study and the ability to combine the data with the results of other studies. All of the studies were biased by their retrospective, nonrandomized nature. DATA SYNTHESIS: Significance (p < 0.05) was determined using the chi2 test. CONCLUSIONS: Cerebrospinal fluid leak occurred in 10.6% of 2,273 retrosigmoid surgeries, 9.5% of 3,118 translabyrinthine surgeries, and 10.6% of 573 middle fossa surgeries. The type of cerebrospinal fluid leak was not associated with surgical approach. Meningitis was significantly associated with cerebrospinal fluid leak (p < 0.05). Age and tumor size were not associated with cerebrospinal fluid leak.     

Empirical determination of thresholds for case identification: Validation of the Personality Diagnostic Questionnaire-Revised

The Personality Diagnostic Questionnaire-Revised (PDQ-R) was sent to first-degree relatives of major psychotic patients for identification of DSM-III-R personality disorders (PDs). Responses to the PDQ-R were interpreted both literally and empirically, and compared with the Structured Interview for DSM-III PDs (SIDP) as the standard. For literal interpretation, symptoms reported were counted directly for case identification using fixed DSM-III-R thresholds. The empirical approach adjusted the threshold for case identification to maximize concordance with the SIDP. Comparison of the two methods showed that using empirically determined thresholds in some scales gives better concordance with the SIDP. For the dependent and histrionic PD scales, the improvements were statistically significant. The area under the receiver operating characteristic (ROC) curve was computed for each PDQ-R scale to summarize its discriminatory capability across all thresholds. Areas under the ROC curve indicated that the schizoid, schizotypal, borderline, dependent, passive-aggressive, and histrionic PD scales in the PDQ-R have better discriminatory qualities than other PDQ-R scales.