Carmelina Chiriaco

Computer-Assisted Cognitive Rehabilitation of Attention Deficits for Multiple Sclerosis: A Randomized Trial With fMRI Correlates

Background. Although a growing body of evidence has highlighted the role of cognitive rehabilitation (CR) in the management of cognitive dysfunctions in multiple sclerosis (MS), there is still no evidence for a validated therapeutic approach. Objective. We propose a new therapeutic strategy characterized by a computer-based intensive attention training program in MS patients with predominant attention deficits. We aim to investigate the effectiveness of our rehabilitation procedure, tailored for those with impaired abilities, using functional magnetic resonance imaging (fMRI). Methods. Using a double-blind randomized controlled study, we enrolled 12 MS patients, who underwent a CR program (experimental group), and 11 age-gender–matched MS patients, who underwent a placebo intervention (control group). fMRI was recorded during the execution of a cognitive task broadly used for assessing attention abilities in MS patients (paced visual serial addition test). Results. Significant effects were detected both at a phenotypic and at an intermediate phenotypic level. After CR, the experimental group, in comparison with the control group, showed a specific enhanced performance in attention abilities as assessed by the Stroop task with an effect size of 0.88, which was associated with increased activity in the posterior cerebellar lobule and in the superior parietal lobule. Conclusions. Our study demonstrates that intensive CR tailored for those with impaired abilities affects neural plasticity and improves some aspects of cognitive deficits in MS patients. The reported neurophysiological and behavioral effects corroborate the benefits of our therapeutic approach, which might have a reliable application in the clinical management of cognitive deficits in MS.

Altered cortical-cerebellar circuits during verbal working memory in essential tremor

Essential tremor is a common neurological disorder characterized by motor and cognitive symptoms including working memory deficits. Epidemiological research has shown that patients with essential tremor are at a higher risk to develop dementia relative to age-matched individuals; this demonstrates that cognitive impairments reflect specific, although poorly understood, disease mechanisms. Neurodegeneration of the cerebellum has been implicated in the pathophysiology of essential tremor itself; however, whether cerebellar dysfunctions relate to cognitive abnormalities is unclear. We addressed this issue using functional neuroimaging in 15 patients with essential tremor compared to 15 sex-, education- and age-matched healthy controls while executing a verbal working memory task. To remove confounding effects, patients with integrity of the nigrostriatal terminals, no dementia and abstinent from medications altering cognition were enrolled. We tested whether patients displayed abnormal activations of the cerebellum (posterior lobules) and other areas typically engaged in working memory (dorsolateral prefrontal cortex, parietal lobules). Between-groups differences in the interactions of these regions were also assessed with functional connectivity methods. Finally, we determined whether individual differences in neuropsychological and clinical measures modulated the magnitude of regional brain responses and functional connectivity data in patients with essential tremor. Despite similar behavioural performances, patients showed greater cerebellar response (crus I/lobule VI) compared to controls during attentional-demanding working memory trials (F = 8.8; P < 0.05, corrected). They also displayed altered functional connectivity between crus I/lobule VI and regions implicated in focusing attention (executive control circuit including dorsolateral prefrontal cortex, inferior parietal lobule, thalamus) and in generating distracting self-related thoughts (default mode network including precuneus, ventromedial prefrontal cortex and hippocampus) (T-values > 3.2; P < 0.05, corrected). These findings were modulated by the variability in neuropsychological measures: patients with low cognitive scores displayed reduced connectivity between crus I/lobule VI and the dorsolateral prefrontal cortex and enhanced connectivity between crus I/lobule VI and the precuneus (T-values > 3.7; P < 0.05, corrected). It is likely that cerebellar neurodegeneration underlying essential tremor is reflected in abnormal communications between key regions responsible for working memory and that adaptive mechanisms (enhanced response of crus I/lobule VI) occur to limit the expression of cognitive symptoms. The connectivity imbalance between the executive control circuit and the default mode network in patients with essential tremor with low cognitive scores may represent a dysfunction, driven by the cerebellum, in suppressing task irrelevant thoughts via focused attention. Overall, our results offer new insights into pathophysiological mechanisms of cognition in essential tremor and suggest a primary role of the cerebellum in mediating abnormal interactions between the executive control circuit and the default mode network.

Cognitive deficits in multiple sclerosis patients with cerebellar symptoms

Background Cerebellar dysfunction is common in patients with multiple sclerosis (MS). However, neuropsychological studies of this clinical feature are lacking. Objective We investigate the neuropsychological features in relapsing-remitting MS (RR-MS) patients with and without cerebellar dysfunction. Methods Twenty-one RR-MS patients with cerebellar dysfunction (RR-MSc), characterized by prevalent ataxic gait and nystagmus, and 21 RR-MS patients without any cerebellar manifestation (RR-MSnc) pair-matched for demographical and clinical variables were studied. All patients from each group underwent an extensive battery of neuropsychological tests. Magnetic resonance imaging analysis included hyperintense fast fluid-attenuated inversion-recovery lesion load in the whole brain as well as in the four lobes separately. Results Any significant differences were detected in total and regional lesion load measurements between the two groups. RR-MSc group performed equally as well as the RR-MSnc group on many of the cognitive exploration measures. Nevertheless, the RR-MSc group performed more poorly than the RR-MSnc group on attention tests (Symbol Digit Modalities Test) and verbal fluency tests (Controlled Oral Word Association Test); neither of the test results proved to be affected by regional lesion loads. Conclusion These results highlight the importance of considering cognitive deficits associated with the presence of cerebellar symptoms in RR-MS.

Brain Iron Deposition in Essential Tremor: A Quantitative 3-Tesla Magnetic Resonance Imaging Study

Studies have demonstrated brain iron deposition in neurodegenerative disease and in normal aging. Data on this topic are lacking in essential tremor (ET). The aim of our study was to investigate brain iron content in patients with ET, using quantitative magnetic resonance imaging (MRI) T2*‐relaxometry. We enrolled 24 patients with ET and 25 age‐matched healthy controls. Subjects were examined using a 3T MRI scanner. The protocol included conventional MRI sequences and quantitative T2*‐relaxometry. Whole‐brain voxel‐based analyses showed significant differences in T2* values in bilateral globus pallidus, substantia nigra, and in right dentate nucleus (P < .001 uncorrected). In the bilateral pallidum, differences survived family‐wise‐error (FWE) correction for multiple comparisons (P < .05). The present study provides the first evidence of increased brain iron accumulation in ET patients. Our results are suggestive of a possible involvement of motor systems outside of the cerebellum/cerebellar pathway and, more specifically, of the globus pallidus.

Neuropsychological disturbances in frontal lobe epilepsy due to mutated nicotinic receptors.

Mutations in nicotinic receptor subunits have been identified in some families with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). Normal intelligence has currently been considered the rule, although anecdotal cases with intellectual disability have been reported. We aimed to evaluate the frequency and degree of neuropsychological disorders in ADNFLE associated with nicotinic receptor mutations by testing 11 subjects from four families with a comprehensive neuropsychological assessment. General intellectual function was below the normal range in 45% of the subjects. All were abnormal in one or more executive task. Memory was either more affected than executive functions or equally affected in two thirds of subjects, suggesting a frontotemporal pattern of cognitive impairment. Cognitive dysfunction appears to be an integral part of the broad phenotype of ADNFLE with nicotinic receptor mutations, a fact that has been underestimated until now. The cognitive disorder affects executive functions as well as memory in most subjects.

Cortical volume and folding abnormalities in Parkinson's disease patients with pathological gambling

PURPOSE Pathological gambling (PG) is one of the most devastating non-motor complications of Parkinsons disease (PD). Neuroanatomical abnormalities in PD patients with PG are poorly understood. METHODS In the current study we investigated PD patients with and without PG using Voxel Based Morphometry (VBM) and local Gyrification Index (lGI), two neuroimaging techniques useful for detecting complementary morphological metrics in the brain. Twelve PD patients with PG were compared to 12 clinically-matched PD patients without PG and 24 healthy controls. RESULTS PD patients with PG showed grey matter volume loss specifically in the orbitofrontal cortex (OFC) when compared to patients without PG, with the atrophy of this region correlating with the increase of gambling symptoms (G-SAS). Surface-based analysis complemented this evidence revealing that the OFC in the PD patients with PG was also characterized by a reduced lGI. Moreover, when compared to controls, PD patients with PG showed a more widespread anatomical neurodegeneration involving several limbic regions such as: the OFC, cingulate cortex, inferior frontal cortex and insular cortex. Otherwise, demographically-/clinically-matched PD patients without PG did not display significant anatomical changes. DISCUSSION Our study demonstrates that combined grey matter atrophy and reduced lGI in the OFC differentiates PD patients with PG from those without PG, suggesting that this cortical area may play a critical role in the development of this drug-induced behavioral disorder.

Myocardial 123I-MIBG scintigraphy for differentiation of Lewy bodies disease from FTD

Clinical distinction between Lewy bodies disease (LBD) and frontotemporal dementia (FTD) is sometimes difficult. Nigrostriatal dopaminergic degeneration occurs in both LBD and FTD, limiting helpfulness of DAT imaging to differentiate these forms of dementia. Several studies have emphasized the usefulness of myocardial scintigraphy with (123)Metaiodobenzylguanidine ((123)I-MIGB) in assessing the sympathetic nerve terminals in LBD demonstrating that cardiac (123)I-MIGB uptake is decreased in patients with this disease. We investigated the role of cardiac (123)I-MIBG scintigraphy in differentiating patients with LBD from those with FTD. Clinical diagnosis of LBD and FTD was determined according to established consensus criteria. Nine patients with LBD (1 possible and 8 probable), 6 patients with FTD, and 16 control subjects were involved in the study. The heart to mediastinum ratio (H/M) of (123)I-MIBG uptake was markedly reduced in all patients with LBD (H/M early: 1.25±0.12; delayed: 1.14±0.13) whereas it was normal in patients with FTD (H/M early: 1.86±0.20; delayed: 1.80±0.23) and in controls (H/M early: 1.91±0.17; delayed: 1.99±0.19), suggesting that cardiac (123)I-MIBG scintigraphy can help distinguish patients with LBD from those with FTD.

Dopamine‐transporter levels drive striatal responses to apomorphine in Parkinson's disease

Dopaminergic therapy in Parkinsons disease (PD) can improve some cognitive functions while worsening others. These opposite effects might reflect different levels of residual dopamine in distinct parts of the striatum, although the underlying mechanisms remain poorly understood. We used functional magnetic resonance imaging (fMRI) to address how apomorphine, a potent dopamine agonist, influences brain activity associated with working memory in PD patients with variable levels of nigrostriatal degeneration, as assessed via dopamine‐transporter (DAT) scan. Twelve PD patients underwent two fMRI sessions (Off‐, On‐apomorphine) and one DAT‐scan session. Twelve sex‐, age‐, and education‐matched healthy controls underwent one fMRI session. The core fMRI analyses explored: (1) the main effect of group; (2) the main effect of treatment; and (3) linear and nonlinear interactions between treatment and DAT levels. Relative to controls, PD‐Off patients showed greater activations within posterior attentional regions (e.g., precuneus). PD‐On versus PD‐Off patients displayed reduced left superior frontal gyrus activation and enhanced striatal activation during working‐memory task. The relation between DAT levels and striatal responses to apomorphine followed an inverted‐U‐shaped model (i.e., the apomorphine effect on striatal activity in PD patients with intermediate DAT levels was opposite to that observed in PD patients with higher and lower DAT levels). Previous research in PD demonstrated that the nigrostriatal degeneration (tracked via DAT scan) is associated with inverted‐U‐shaped rearrangements of postsynaptic D2‐receptors sensitivity. Hence, it can be hypothesized that individual differences in DAT levels drove striatal responses to apomorphine via D2‐receptor‐mediated mechanisms.

The relationship between regional microstructural abnormalities of the corpus callosum and physical and cognitive disability in relapsing-remitting multiple sclerosis.

Significant corpus callosum (CC) involvement has been found in relapsing–remitting multiple sclerosis (RRMS), even if conventional magnetic resonance imaging measures have shown poor correlation with clinical disability measures. In this work, we tested the potential of multimodal imaging of the entire CC to explain physical and cognitive disability in 47 patients with RRMS. Values of thickness, fractional anisotropy (FA) and mean diffusivity (MD) were extracted from 50 regions of interest (ROIs) sampled along the bundle. The relationships between clinical, neuropsychological and imaging variables were assessed by using Spearmans correlation. Multiple linear regression analysis was employed in order to identify the relative importance of imaging metrics in modeling different clinical variables. Regional fiber composition of the CC differentially explained the response variables (Expanded Disability Status Scale [EDSS], cognitive impairment). Increases in EDSS were explained by reductions in CC thickness and MD. Cognitive impairment was mainly explained by FA reductions in the genu and splenium. Regional CC imaging properties differentially explained disability within RRMS patients revealing strong, distinct patterns of correlation with clinical and cognitive status of patients affected by this specific clinical phenotype.

Effect of aging on magnetic resonance measures differentiating progressive supranuclear palsy from Parkinson's disease

Imaging measurements, such as the ratio of the midsagittal areas of the midbrain and pons (midbrain/pons) and the Magnetic Resonance Parkinsonism Index (MRPI), have been proposed to differentiate progressive supranuclear palsy (PSP) from Parkinsons disease (PD). However, abnormal midbrain/pons values suggestive of PSP have also been reported in elderly individuals and in patients with PD. We investigated the effect of aging on single or combined imaging measurements of the brainstem. We calculated the midbrain/pons and the MRPI (the ratio of the midsagittal areas of the pons and the midbrain multiplied by the ratio of the middle cerebellar peduncle and superior cerebellar peduncle widths) in 152 patients affected by PD, 25 patients with PSP, and a group of 81 age‐matched and sex‐matched healthy controls using a 3‐Tesla magnetic resonance imaging scanner. In healthy controls, aging was negatively correlated with midsagittal area of the midbrain and midbrain/pons values. In patients with PD, in addition to the effect of aging, the disease status further influenced the midbrain/pons values (R2 = 0.23; P < 0.001). In both groups, MRPI values were not influenced either by aging or by disease status. No effect of aging on either midbrain/pons or MRPI values was shown in the patients with PSP. Our findings indicated that the MRPI was not significantly influenced by aging or disease‐related changes occurring in PD; whereas, in contrast, the midbrain/pons was influenced. Therefore, the MRPI appears to be a more reliable imaging measurement compared with midbrain/pons values for differentiating PSP from PD and controls in an elderly population.