Search

Brain tumors are a rare disease, however the cost in term of unfavorable prognosis and impact on quality of life is very high. The complex treatment requested by a brain tumor (surgery and pharmacological therapy) may determine neurological and cognitive consequences, that need an immediate and precise intervention. For this reason, novel diagnostic methods that combine behavioral and imaging data are requested. This research work was aimed at investigating cognitive and imaging correlates of brain tumors and is built on different aims. The first goal was the definition of the neuropsychological profile of brain tumors. We specifically focused on cognitive deficits associated with the pathophysiology of the tumor. In other words, we investigated if brain tumors may cause a specific type of cognitive damage, based on the specific pathophysiological behavior in affecting the brain. To this end, an observational study was designed and the assessment of a cohort of brain tumor patients in the pre-operative stage was performed. By means of an extensive neuropsychological protocol, patients were evaluated in different cognitive domains. This study allows us to describe the cognitive features of the tumors, by taking into account some physiological variables: type of tumor (e.g. glioma vs meningioma), site of the lesion, extension of the lesion. To the best of our knowledge, no study so far has defined the cognitive profile of brain tumors taking in account the specific neurological nature of this pathology, in order to define a suitable neuropsychological battery for the cognitive characterization of brain tumors. The second aim concerned precisely the effort to define the specificity of the neuropsychological battery in detecting the particular cognitive disease consequent to brain tumors. To achieve this goal, we compared the neuropsychological performance of the group of patients with brain tumor with a group of patients with focal stroke, a neurological disorder involving a very different pathophysiological process. This implies the identification of the neuropsychological tests that are sensitive in detecting the specific as well as subtle cognitive deficits consequent to brain tumors. 7 The third aim had a longitudinal perspective and concerned the study of the effects of tumor resection on cognitive functions in the long term. To achieve this goal, we analyzed the behavioral data of the group of patients at three different time points: pre-surgical, post-surgical and one month follow-up. We expected a global worsening of the cognitive scores in the immediate post-operative stage, with a subsequent recovery at one month follow-up. A preliminary study was also conducted in order to define the effect of the treatment (radiotherapy and chemotherapy) on cognitive functions, with the aim to clarify the interaction of surgery and treatment in affecting the brain. Hence a further follow-up was also conducted four months from the neurosurgery and after the therapy. Importantly, this study clarified the interaction between the cognitive effects of the treatment and surgical intervention. Furthermore, it shed light on the relevance of follow-up neuropsychological assessment in monitoring brain tumors. The present doctoral thesis aimed at clarifying the contribution of neuropsychological as well as neuroimaging measures in order to better characterize the specific pathophysiological processes beneath functional and cognitive symptoms. For this reason, a further effort consisted in exploring structural and functional neuroimaging biomarkers able to predict the patient’s quality of life after tumor surgical resection. We furthermore aimed to assess the added value of the use of local and global brain connectivity in the clinical decision process. To this end, together with the neuropsychological evaluation, metabolism and perfusion data were longitudinally acquired, using simultaneous dynamic PET and MRI techniques. These data were acquired before surgery, after one month, and after three months from surgery. This study is still ongoing. The overarching goal in the long term of the whole research is to take into account together neuroplasticity and neuropsychological aspects in neuro-oncology in order to create a new way of taking care of patients with brain tumor. Of note, the correlation between tumor variables, behavioral outcome and structural, functional, and metabolic metrics of brain organization allows individualized planning of surgery and treatment. This planning will therefore be tailored considering the characteristics of the single patient, leading to a better outcome and a reduced impact on functions and quality of life.

Dopamine systems mediate key aspects of reward learning. Parkinson’s disease (PD) represents a valuable model to study reward mechanisms because both the disease process and the anti-Parkinson medications influence dopamine neurotransmission. The aim of this pilot study was to investigate whether the level of levodopa differently modulates learning from positive and negative feedback and its electrophysiological correlate, the error related negativity (ERN), in PD. Ten PD patients and ten healthy participants performed a two-stage reinforcement learning task. In the Learning Phase, they had to learn the correct stimulus within a stimulus pair on the basis of a probabilistic positive or negative feedback. Three sets of stimulus pairs were used. In the Testing Phase, the participants were tested with novel combinations of the stimuli previously experienced to evaluate whether they learned more from positive or negative feedback. PD patients performed the task both ON- and OFF-levodopa in two separate sessions while they remained on stable therapy with dopamine agonists. The electroencephalogram (EEG) was recorded during the task. PD patients were less accurate in negative than positive learning both OFF- and ON-levodopa. In the OFF-levodopa state they were less accurate than controls in negative learning. PD patients had a smaller ERN amplitude OFF- than ON-levodopa only in negative learning. In the OFF-levodopa state they had a smaller ERN amplitude than controls in negative learning. We hypothesize that high tonic dopaminergic stimulation due to the dopamine agonist medication, combined to the low level of phasic dopamine due to the OFF-levodopa state, could prevent phasic “dopamine dips” indicated by the ERN needed for learning from negative feedback.

The aim of this study was to build an instrument, the numerical activities of daily living (NADL), designed to identify the specific impairments in numerical functions that may cause problems in everyday life. These impairments go beyond what can be inferred from the available scales evaluating activities of daily living in general, and are not adequately captured by measures of the general deterioration of cognitive functions as assessed by standard clinical instruments like the MMSE and MoCA. We assessed a control group (n = 148) and a patient group affected by a wide variety of neurological conditions (n = 175), with NADL along with IADL, MMSE, and MoCA. The NADL battery was found to have satisfactory construct validity and reliability, across a wide age range. This enabled us to calculate appropriate criteria for impairment that took into account age and education. It was found that neurological patients tended to overestimate their abilities as compared to the judgment made by their caregivers, assessed with objective tests of numerical abilities.

Though the assessment of cognitive functions is proven to be a reliable prognostic indicator in patients with brain tumors, some of these functions, such as cognitive control, are still rarely investigated. The objective of this study was to examine proactive and reactive control functions in patients with focal brain tumors and to identify lesioned brain areas more at "risk" for developing impairment of these functions. To this end, a group of twenty-two patients, candidate to surgery, were tested with an AX-CPT task and a Stroop task, along with a clinical neuropsychological assessment, and their performance was compared to that of a well-matched healthy control group. Although overall accuracy and response times were similar for patients and control groups, the patient group failed more on the BX trials of the AX-CPT task and on the incongruent trials of the Stroop task, specifically. Behavioral results were associated with the damaged brain areas, mostly distributed in right frontal regions, by means of a lesion-symptom mapping multivariate approach. This analysis showed that a white matter cluster in the right prefrontal area was associated with lower d'-context values on the AX-CPT, which reflected the fact that these patients rely more on later information (reactive processes) to respond to unexpected and conflicting stimuli, than on earlier contextual cues (proactive processes). Taken together, these results suggest that patients with brain tumors present an imbalance between proactive and reactive control strategies in high interfering conditions, in association with right prefrontal white matter lesions.

ObjectiveOur aim was to perform an updated systematic review and meta-analysis on the efficacy and safety of adjunctive minocycline as a treatment of schizophrenia.MethodsWe conducted a PubMed/Scopus database search from inception to 3 February 2016 for randomized, placebo-controlled trials (RCTs), open non-randomized studies, and case reports/series evaluating minocycline in patients with schizophrenia. Random-effects meta-analysis of positive, negative, depressive, and cognitive symptom rating scales, discontinuation and adverse effects rates calculating standardized mean difference (SMD), and risk ratios±95% confidence intervals (CI95%) were calculated.ResultsSix RCTs were eligible (minocyclinen=215, placebon=198) that demonstrated minocycline’s superiority versus placebo for reducing endpoint Positive and Negative Syndrome Scale (PANSS) total scores (SMD=–0.59;CI95%=[1.15, –0.03];p=0.04), negative (SMD=–0.76;CI95%=[–1.21, –0.31];p=0.001); general subscale scores (SMD=–0.44;CI95%=[–0.88, –0.00];p=0.05), Clinical Global Impressions scores (SMD=–0.50;CI95%=[–0.78, –0.22];pSMD=0.22;CI95%=[0.01, 0.44];p=0.04). Endpoint PANSS positive symptom scores (p=0.13), depression rating scale scores (p=0.43), attention (p=0.47), memory (p=0.52), and motor speed processing (p=0.50) did not significantly differ from placebo, before execution of a trim-and-fill procedure. Minocycline did not differ compared to placebo on all-cause discontinuation (p=0.56), discontinuation due to inefficacy (p=0.99), and intolerability (p=0.51), and due to death (p=0.32). Data from one open-label study (N=22) and three case series (N=6) were consistent with the metaanalytic results.ConclusionsMinocycline appears to be an effective adjunctive treatment option in schizophrenia, improving multiple relevant disease dimensions. Moreover, minocycline has an acceptable safety and tolerability profile. However, more methodologically sound and larger RCTs remain necessary to confirm and extend these results.