Cristina Scarpazza

Prognostic prediction of therapeutic response in depression using high-field MR imaging

Despite significant advances in the treatment of major depression, there is a high degree of variability in how patients respond to treatment. Approximately 70% of patients show some improvement following standard antidepressant treatment and are classified as having non-refractory depressive disorder (NDD), while the remaining 30% of patients do not respond to treatment and are classified as having refractory depressive disorder (RDD). At present, there are no objective, neurological markers which can be used to identify individuals with depression and predict clinical outcome. We therefore examined the diagnostic and prognostic potential of pre-treatment structural neuroanatomy using support vector machine (SVM). Sixty-one drug-naïve adults suffering from depression and 42 healthy volunteers were scanned using structural magnetic resonance imaging (sMRI). Patients then received standard antidepressant medication (either tricyclic, typical serotonin-norepinephrine reuptake inhibitor or typical selective serotonin reuptake inhibitor). Based on clinical outcome, we selected two groups of RDD (n=23) and NDD (n=23) patients matched for age, sex and pre-treatment severity of depression. Diagnostic accuracy of gray matter was 67.39% for RDD (p=0.01) and 76.09% for NDD (p<0.001), while diagnostic accuracy of white matter was 58.70% for RDD (p=0.13) and 84.65% for NDD (p<0.001). SVM applied to gray matter correctly distinguished between RDD and NDD patients with an accuracy of 69.57% (p=0.006); in contrast, SVM applied to white matter predicted clinical outcome with an accuracy of 65.22% (p=0.02). These results indicate that both gray and white matter have diagnostic and prognostic potential in major depression and may provide an initial step towards the use of biological markers to inform clinical treatment. Future studies will benefit from the integration of structural neuroimaging with other imaging modalities as well as genetic, clinical and cognitive information.

When the single matters more than the group: very high false positive rates in single case Voxel Based Morphometry.

Voxel Based Morphometry (VBM) studies typically involve a comparison between groups of individuals; this approach however does not allow inferences to be made at the level of the individual. In recent years, an increasing number of research groups have attempted to overcome this issue by performing single case studies, which involve the comparison between a single subject and a control group. However, the interpretation of the results is problematic; for instance, any significant difference might be driven by individual variability in neuroanatomy rather than the neuropathology of the disease under investigation, or might represent a false positive due to the data being sampled from non-normally distributed populations. The aim of the present investigation was to empirically estimate the likelihood of detecting significant differences in gray matter volume in individuals free from neurological or psychiatric diagnosis. We compared a total of 200 single subjects against a group of 16 controls matched for age and gender, using two independent datasets from the Neuroimaging Informatics Tools and Resources Clearinghouse. We report that the chance of detecting a significant difference in a disease-free individual is much higher than previously expected; for instance, using a standard voxel-wise threshold of p<0.05 (corrected) and an extent threshold of 10 voxels, the likelihood of a single subject showing at least one significant difference is as high as 93.5% for increases and 71% for decreases. We also report that the chance of detecting significant differences was greatest in frontal and temporal cortices and lowest in subcortical regions. The chance of detecting significant differences was inversely related to the degree of smoothing applied to the data, and was higher for unmodulated than modulated data. These results were replicated in the two independent datasets. By providing an empirical estimation of the number of significant increases and decreases to be expected in each cortical and subcortical region in disease-free individuals, the present investigation could inform the interpretation of future single case VBM studies.

Natalizumab-related progressive multifocal leukoencephalopathy in multiple sclerosis: Findings from an Italian independent registry

Background The monoclonal antibody natalizumab (NTZ) is a highly effective treatment for patients with multiple sclerosis (MS). However, this drug is associated with increased risk of developing Progressive Multifocal Leukoencephalopathy (PML), an opportunistic infection of central nervous system (CNS) caused by the John Cunningham polyomavirus (JCV). Objective To describe the 12-month clinical course of 39 patients with MS (28 women, 11 men) who developed NTZ-related PML after a mean exposure of 39 infusions. Methods An Italian independent collaborative repository initiative collected and analyzed socio-demographic, clinical, magnetic resonance imaging (MRI) data and number of JCV-DNA copies detected on cerebrospinal fluid (CSF) samples of patients diagnosed as affected by NTZ-related PML. The evolution of disability, measured by the Expanded Disability Status Scale, was assessed at NTZ start, at PML diagnosis and after 2, 6 and 12 months from PML diagnosis. The effect of clinical and paraclinical characteristics at PML diagnosis on the final outcome was also investigated. Results Ten patients (25.6%) were diagnosed before 24 NTZ infusions. In six cases (15.4%) the PML suspect was made on the basis of highly suggestive MRI findings in absence of any detectable change of clinical conditions (asymptomatic PML). In patients with symptomatic PML, the diagnosis was quicker for those who presented with cognitive symptoms (n = 12) rather than for those with other neurological pictures (n = 21) (p = 0.003). Three patients (7.7%) died during the 12-month observation period, resulting in a survival rate of 92.3%. Asymptomatic PML, more localized brain involvement and gadolinium-enhancement detected at MRI, as well as lower viral load were associated with a better disability outcome (p-values<0.01). Conclusion Our findings support that early PML diagnosis, limited CNS involvement and initial signs of immune restoration are associated with a better outcome and higher survival rate, and confirm the utility of MRI as a surveillance tool for NTZ-treated patients.

False positive rates in Voxel-based Morphometry studies of the human brain: Should we be worried?

Voxel-based Morphometry (VBM) is a widely used automated technique for the analysis of neuroanatomical images. Despite its popularity within the neuroimaging community, there are outstanding concerns about its potential susceptibility to false positive findings. Here we review the main methodological factors that are known to influence the results of VBM studies comparing two groups of subjects. We then use two large, open-access data sets to empirically estimate false positive rates and how these depend on sample size, degree of smoothing and modulation. Our review and investigation provide three main results: (i) when groups of equal size are compared false positive rate is not higher than expected, i.e. about 5%; (ii) the sample size, degree of smoothing and modulation do not appear to influence false positive rate; (iii) when they exist, false positive findings are randomly distributed across the brain. These results provide reassurance that VBM studies comparing groups are not vulnerable to the higher than expected false positive rates that are evident in single case VBM.

Early Aphasia Rehabilitation Is Associated With Functional Reactivation of the Left Inferior Frontal Gyrus: A Pilot Study

Background and Purpose— Early poststroke aphasia rehabilitation effects and their functional MRI (fMRI) correlates were investigated in a pilot, controlled longitudinal study. Methods— Twelve patients with mild/moderate aphasia (8 Broca, 3 anomic, and 1 Wernicke) were randomly assigned to daily language rehabilitation for 2 weeks (starting 2.2 [mean] days poststroke) or no rehabilitation. The Aachen Aphasia Test and fMRI recorded during an auditory comprehension task were performed at 3 time intervals: mean 2.2 (T1), 16.2 (T2), and 190 (T3) days poststroke. Results— Groups did not differ in terms of age, education, aphasia severity, lesions volume, baseline fMRI activations, and in task performance during fMRI across examinations. Rehabilitated patients significantly improved in naming and written language tasks (P<0.05) compared with no rehabilitation group both at T2 and T3. Functional activity at T1 was reduced in language-related cortical areas (right and left inferior frontal gyrus and middle temporal gyrus, right inferior parietal lobule and superior temporal gyrus) in patients compared with controls. T2 and T3 follow-ups revealed a cortical activation increase, with significantly greater activation in the left hemisphere areas in rehabilitated patients at T2 and T3, and a time×treatment effect at T2 in the left inferior Broca area after rehabilitation. Left inferior frontal gyrus activation at T2 significantly correlated with naming improvement. Conclusions— Early poststroke aphasia treatment is useful, has durable effects, and may lead to early enhanced recruitment of brain areas, particularly the left inferior frontal gyrus, which persists in the chronic phase.

Natalizumab Significantly Improves Cognitive Impairment over Three Years in MS: Pattern of Disability Progression and Preliminary MRI Findings

Previous studies reported that Multiple Sclerosis (MS) patients treated with natalizumab for one or two years exhibit a significant reduction in relapse rate and in cognitive impairment, but the long term effects on cognitive performance are unknown. This study aimed to evaluate the effects of natalizumab on cognitive impairment in a cohort of 24 consecutive patients with relapsing remitting MS treated for 3 years. The neuropsychological tests, as well as relapse number and EDSS, were assessed at baseline and yearly for three years. The impact on cortical atrophy was also considered in a subgroup of them, and are thus to be considered as preliminary. Results showed a significant reduction in the number of impaired neuropsychological tests after three years, a significant decrease in annualized relapse rate at each time points compared to baseline and a stable EDSS. In the neuropsychological assessment, a significant improvement in memory, attention and executive function test scores was detected. Preliminary MRI data show that, while GM volume did not change at 3 years, a significantly greater parahippocampal and prefrontal gray matter density was noticed, the former correlating with neuropsychological improvement in a memory test. This study showed that therapy with Natalizumab is helpful in improving cognitive performance, and is likely to have a protective role on grey matter, over a three years follow-up.

The Rao’s Brief Repeatable Battery version B: normative values with age, education and gender corrections in an Italian population

The Brief Repeatable Battery (BRB) of Neuropsychological Tests is one of the most widely used instruments to assess cognitive functioning in multiple sclerosis patients. However, to date, normative data for the Italian population are available only for the version A, which limits the use of the battery in longitudinal evaluations. We administered the BRB version B to 132 healthy subjects to obtain normative values taking into account the influences of demographic factors on the test scores and calculating corrections for these relevant factors (age, gender and education). Higher age and educational level were associated with better performance on all the tests. The World List Generation was also influenced by gender, since women performed better than men. Moreover, some tests of the version B seem to be easier than those of version A. Our data can improve the applicability of the BRB for both clinical and research purposes in longitudinal assessments.

Effects of cue focality on the neural mechanisms of prospective memory: A meta-analysis of neuroimaging studies

Remembering to execute pre-defined intentions at the appropriate time in the future is typically referred to as Prospective Memory (PM). Studies of PM showed that distinct cognitive processes underlie the execution of delayed intentions depending on whether the cue associated with such intentions is focal to ongoing activity processing or not (i.e., cue focality). The present activation likelihood estimation (ALE) meta-analysis revealed several differences in brain activity as a function of focality of the PM cue. The retrieval of intention is supported mainly by left anterior prefrontal cortex (Brodmann Area, BA 10) in nonfocal tasks, and by cerebellum and ventral parietal regions in focal tasks. Furthermore, the precuneus showed increased activation during the maintenance phase of intentions compared to the retrieval phase in nonfocal tasks, whereas the inferior parietal lobule showed increased activation during the retrieval of intention compared to maintenance phase in the focal tasks. Finally, the retrieval of intention relies more on the activity in anterior cingulate cortex for nonfocal tasks, and on posterior cingulate cortex for focal tasks. Such focality-related pattern of activations suggests that prospective remembering is mediated mainly by top-down and stimulus-independent processes in nonfocal tasks, whereas by more automatic, bottom-up, processes in focal tasks.

A Neuroanatomical Signature for Schizophrenia Across Different Ethnic Groups

Schizophrenia is a disabling clinical syndrome found across the world. While the incidence and clinical expression of this illness are strongly influenced by ethnic factors, it is unclear whether patients from different ethnicities show distinct brain deficits. In this multicentre study, we used structural Magnetic Resonance Imaging to investigate neuroanatomy in 126 patients with first episode schizophrenia who came from 4 ethnically distinct cohorts (White Caucasians, African-Caribbeans, Japanese, and Chinese). Each patient was individually matched with a healthy control of the same ethnicity, gender, and age (±1 year). We report a reduction in the gray matter volume of the right anterior insula in patients relative to controls (P < .05 corrected); this reduction was detected in all 4 ethnic groups despite differences in psychopathology, exposure to antipsychotic medication and image acquisition sequence. This finding provides evidence for a neuroanatomical signature of schizophrenia expressed above and beyond ethnic variations in incidence and clinical expression. In light of the existing literature, implicating the right anterior insula in bipolar disorder, depression, addiction, obsessive-compulsive disorder, and anxiety, we speculate that the neuroanatomical deficit reported here may represent a transdiagnostic feature of Axis I disorders.

To do or not to do? plasma exchange and timing of steroid administration in progressive multifocal leukoencephalopathy

To retrospectively analyze the effect of plasma exchange (PLEX; yes = PLEX+, no = PLEX–) and steroids administration timing (prophylactically [proST] or therapeutically [therST]) on the longitudinal clinical course of patients with natalizumab‐related progressive multifocal leukoencephalopathy (PML) and full‐blown immune reconstitution inflammatory syndrome (PML‐IRIS).