Federico Rocca

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.

Automatic Detection of White Matter Hyperintensities in Healthy Aging and Pathology Using Magnetic Resonance Imaging: A Review

White matter hyperintensities (WMH) are commonly seen in the brain of healthy elderly subjects and patients with several neurological and vascular disorders. A truly reliable and fully automated method for quantitative assessment of WMH on magnetic resonance imaging (MRI) has not yet been identified. In this paper, we review and compare the large number of automated approaches proposed for segmentation of WMH in the elderly and in patients with vascular risk factors. We conclude that, in order to avoid artifacts and exclude the several sources of bias that may influence the analysis, an optimal method should comprise a careful preprocessing of the images, be based on multimodal, complementary data, take into account spatial information about the lesions and correct for false positives. All these features should not exclude computational leanness and adaptability to available data.

Structural 'connectomic' alterations in the limbic system of multiple sclerosis patients with major depression

Background: Major depression (MD) is a common psychiatric disorder in multiple sclerosis (MS). Despite the negative impact of MD on the quality of life of MS patients, little is known about its underlying brain mechanisms. Objective: We studied the whole-brain connectivity patterns that were associated with MD in MS. Alterations were mainly expected within limbic circuits. Methods: Diffusion tensor imaging data were collected in 20 MS patients with MD, 22 non-depressed MS patients and 16 healthy controls. We used deterministic tractography and graph analysis to study the white-matter connectivity patterns that characterized MS patients with MD. Results: We found that MD in MS was associated with increased local path length in the right hippocampus and right amygdala. Further analyses revealed that these effects were driven by an increased shortest distance between both the right hippocampus and right amygdala and a series of regions including the dorsolateral and ventrolateral prefrontal cortex, orbitofrontal cortex, sensory-motor cortices and supplementary motor area. Conclusion: Our data provide strong support for neurobiological accounts positing that MD in MS is mediated by abnormal ‘communications’ within limbic circuits. We also found evidence that MD in MS may be linked with connectivity alterations at the limbic-motor interface, a group of regions that translates emotions into survival-oriented behaviors.

Tractography in amyotrophic lateral sclerosis using a novel probabilistic tool: A study with tract-based reconstruction compared to voxel-based approach

BACKGROUND Diffusion tensor imaging (DTI) is one of the most sensitive MRI tools for detecting subtle cerebral white matter abnormalities in amyotrophic lateral sclerosis (ALS). Nowadays a plethora of DTI tools have been proposed, but very few methods have been translated into clinical practice. NEW METHOD The aim of this study is to validate the objective measurement of fiber tracts as provided by a new unbiased and automated tractography reconstruction tool named as TRActs Constrained by UnderLying Anatomy (TRACULA). The reliability of this tract-based approach was evaluated on a dataset of 14 patients with definite ALS compared with 14 age/sex-matched healthy controls. To further corroborate these measurements, we used a well-known voxelwise approach, called tract-based spatial statistics (TBSS), on the same dataset. RESULTS TRACULA showed specific significant alterations of several DTI parameters in the corticospinal tract of the ALS group with respect to controls. COMPARISON WITH EXISTING METHOD The same finding was detected using the well-known TBSS analysis. Similarly, both methods depicted also additional microstructural changes in the cingulum. CONCLUSIONS DTI tractography metrics provided by TRACULA perfectly agree with those previously reported in several post-mortem and DTI studies, thus demonstrating the accuracy of this method in characterizing the microstructural changes occurring in ALS. With further validation (i.e. considering the heterogeneity of other clinical phenotypes), this method has the potential to become useful for clinical practice providing objective measurements that might aid radiologists in the interpretation of MR images and improve diagnostic accuracy of ALS.

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.

Hippocampal Subfield Atrophies in Converted and Not-Converted Mild Cognitive Impairments Patients by a Markov Random Fields Algorithm

Although measurement of total hippocampal volume is considered as an important hallmark of Alzheimers disease (AD), recent evidence demonstrated that atrophies of hippocampal subregions might be more sensitive in predicting this neurodegenerative disease. The vast majority of neuroimaging papers investigating this topic are focused on the difference between AD and patients with mild cognitive impairment (MCI), not considering the impact of MCI patients who will or not convert in AD. For this reason, the aim of this study was to determine if measurements of hippocampal subfields provide advantages over total hippocampal volume for discriminating these groups. Hippocampal subfields volumetry was extracted in 55 AD, 32 converted and 89 not-converted MCI (c/nc-MCI) and 47 healthy controls, using an atlas-based automatic algorithm based on Markov random fields embedded in the Freesurfer framework. To evaluate the impact of hippocampal atrophy in discriminating the insurgence of AD-like phenotypes we used three classification methods: Support Vector Machine, Naïve Bayesian Classifier and Neural Networks Classifier. Taking into account only the total hippocampal volume, all classification models, reached a sensitivity of about 66% in discriminating between c-MCI and nc-MCI. Otherwise, classification analysis considering all segmenting subfields increased accuracy to diagnose c-MCI from 68% to 72%. This effect resulted to be strongly dependent upon atrophies of the subiculum and presubiculum. Our multivariate analysis revealed that the magnitude of the difference considering hippocampal subfield volumetry, as segmented by the considered atlas-based automatic algorithm, offers an advantage over hippocampal volume in distinguishing early AD from nc-MCI.

Magnetic Resonance Parkinsonism Index and midbrain to pons ratio: Which index better distinguishes Progressive Supranuclear Palsy patients with a low degree of diagnostic certainty from patients with Parkinson Disease?

INTRODUCTION Several studies have compared the performances of midbrain to pons area ratio (M/P) and the Magnetic Resonance Parkinsonism Index (MRPI) in distinguishing patients with Progressive Supranuclear Palsy (PSP) from those with Parkinsons disease (PD) with conflicting results. The current study aimed to compare the performance of these indexes in a well-characterized sample of PSP patients using either a manual or a fully automated approach to measure the brainstem structures involved in M/P and MRPI calculation. METHODS This study involved 179 patients affected by idiopathic PD, 35 patients affected by PSP (15 probable and 20 possible) and 87 healthy controls. Sensitivity, specificity, positive predictive value (PPV) and area under the curve (AUC) of MRPI and M/P in distinguishing possible and probable PSP from PD and controls were calculated. RESULTS No significant difference was found between manual and automated values for both MRPI and M/P. MRPI and M/P differentiated probable PSP from PD with similar performance. By contrast, MRPI showed higher sensitivity and specificity than M/P when patients with possible PSP were compared with PD (MRPI, sensitivity 100%, specificity 98.88%; M/P, sensitivity 85%, specificity 93.85%). A significant difference was also observed in AUC between MRPI and M/P in distinguishing possible PSP from PD. CONCLUSION Our study demonstrates that MRPI was more accurate than M/P, in differentiating patients with possible PSP from those with PD. In patients suspected of having PSP with a low level of clinic diagnostic accuracy, MRPI should be preferred to M/P for distinguishing these patients from PD.

Exoskeleton-Robot Assisted Therapy in Stroke Patients: A Lesion Mapping Study

Background: Technology-supported rehabilitation is emerging as a solution to support therapists in providing a high-intensity, repetitive and task-specific treatment, aimed at improving stroke recovery. End-effector robotic devices are known to positively affect the recovery of arm functions, however there is a lack of evidence regarding exoskeletons. This paper evaluates the impact of cerebral lesion load on the response to a validated robotic-assisted rehabilitation protocol. Methods: Fourteen hemiparetic patients were assessed in a within-subject design (age 66.9 ± 11.3 years; 10 men and 4 women). Patients, in post-acute phase, underwent 7 weeks of bilateral arm training assisted by an exoskeleton robot combined with a conventional treatment (consisting of simple physical activity together with occupational therapy). Clinical and neuroimaging evaluations were performed immediately before and after rehabilitation treatments. Fugl-Meyer (FM) and Motricity Index (MI) were selected to measure primary outcomes, i.e., motor function and strength. Functional independance measure (FIM) and Barthel Index were selected to measure secondary outcomes, i.e., daily living activities. Voxel-based lesion symptom mapping (VLSM) was used to determine the degree of cerebral lesions associated with motor recovery. Results: Robot-assisted rehabilitation was effective in improving upper limb motor function recovery, considering both primary and secondary outcomes. VLSM detected that lesion load in the superior region of the corona radiata, internal capsule and putamen were significantly associated with recovery of the upper limb as defined by the FM scores (p-level < 0.01). Conclusions: The probability of functional recovery from stroke by means of exoskeleton robotic rehabilitation relies on the integrity of specific subcortical regions involved in the primary motor pathway. This is consistent with previous evidence obtained with conventional neurorehabilitation approaches.

Increased cerebellar gray matter volume in head chefs

Objective Chefs exert expert motor and cognitive performances on a daily basis. Neuroimaging has clearly shown that that long-term skill learning (i.e., athletes, musicians, chess player or sommeliers) induces plastic changes in the brain thus enabling tasks to be performed faster and more accurately. How a chefs expertise is embodied in a specific neural network has never been investigated. Methods Eleven Italian head chefs with long-term brigade management expertise and 11 demographically-/ psychologically- matched non-experts underwent morphological evaluations. Results Voxel-based analysis performed with SUIT, as well as, automated volumetric measurement assessed with Freesurfer, revealed increased gray matter volume in the cerebellum in chefs compared to non-experts. The most significant changes were detected in the anterior vermis and the posterior cerebellar lobule. The magnitude of the brigade staff and the higher performance in the Tower of London test correlated with these specific gray matter increases, respectively. Conclusions We found that chefs are characterized by an anatomical variability involving the cerebellum. This confirms the role of this region in the development of similar expert brains characterized by learning dexterous skills, such as pianists, rock climbers and basketball players. However, the nature of the cellular events underlying the detected morphological differences remains an open question.

PET/CT with 18F–choline: Physiological whole bio-distribution in male and female subjects and diagnostic pitfalls on 1000 prostate cancer patients ☆ ☆☆ ★: 18F–choline PET/CT bio-distribution and pitfalls. A southern Italian experience

INTRODUCTION The 11C/18F-choline is a PET/CT radiopharmaceutical useful in detecting tumors with high lipogenesis. 11C/18F-choline uptake can occur in physiological conditions or tumors. The knowledge of its bio-distribution is essential to recognize physiologic variants or diagnostic pitfalls. Moreover, few information are available on the bio-distribution of this tracer in female patients. Our aim was to discuss some documented 18F-choline PET/CT pitfalls in prostate cancer patients. Our secondary aim was to describe the 18F-choline bio-distribution in the female body. METHODS We collected diagnostic pitfalls in three PET centers examining 1000 prostate cancer by 18F-choline PET/CT. All pitfalls were ensured by follow-up, imaging and/or histology. We also performed whole body 18F-choline PET/CT in 5 female patients. RESULTS 169/1000 (16.9%) patients showed pitfalls not owing to prostate cancer. These findings were due to inflammation, benign tumors while, in 1% of examined patients, a concomitant neoplasm was found. In the female body, the breast showed low physiological uptake. CONCLUSIONS The accurate knowledge of 18F-choline PET/CT bio-distribution and diagnostic pitfalls is essential. Correlative imaging and histological exam are often necessary to depict pitfalls. In women, the uptake in the breast is due to the physiological gradient of 18F-choline uptake in the exocrine glands. ADVANCES IN KNOWLEDGE Our results confirm the possibility of 18F-choline uptake in several diseases other than prostate cancer. However, our experience was acquired on a large population and shows that a conspicuous amount of 18F-choline diagnostic pitfalls are easily recognizable and attributable to inflammation. A new advance in knowledge is the minimal difference in terms of physiological tracer bio-distribution between male and female patients. IMPLICATIONS FOR PATIENT CARE The knowledge of the physiological bio-distribution and of the potential pitfalls linked of a tracer could help physicians to choose the best diagnostic and therapeutic approaches for a better patient quality of life.