Carlo Augusto Mallio

Gadodiamide and Dentate Nucleus T1 Hyperintensity in Patients With Meningioma Evaluated by Multiple Follow-Up Contrast-Enhanced Magnetic Resonance Examinations With No Systemic Interval Therapy.

The dentate nucleus of the cerebellum may appear as hyperintense on unenhanced T1 magnetic resonance images (MRIs) of the brain. Recently, T1 signal hyperintensity has received attention owing to data on the association of this finding with the history of multiple injections of gadolinium-based contrast agents, specifically gadodiamide, in patients with multiple sclerosis and brain metastases. We conducted a retrospective study on patients with a meningioma who had routinely undergone follow-up enhanced MRI scans with gadodiamide. Across a time interval of 18 months (from January 2013 to July 2014), we identified 102 consecutive patients eligible for this study. A significant increase in T1 hyperintensity of the dentate nuclei of the cerebellum on nonenhanced scans was observed between the first and the last MRI in the group of patients with a history of at least 6 enhanced MRI scans (P < 0.01), whereas no differences were observed in the group with 1 to 5 enhanced MRI scans (P = 0.74). Further research is necessary to shed light on the mechanism of the T1 hyperintensity as well as on the histological and microstructural appearance of the dentate nucleus after multiple intravenous injections of gadodiamide. The finding raises the question of substantial dechelation of this agent in patients with normal renal function.

Epicentral Disruption of Structural Connectivity in Alzheimer's Disease

Neurodegenerative changes observed in Alzheimers disease (AD) have been suggested to begin at the entorhinal cortex and hippocampus and then to propagate in a stereotypical fashion. Using diffusion‐weighted imaging, we test whether disruption of structural connectivity in AD is centered on these “epicenters of disease”.

Acute Modulation of Brain Connectivity in Parkinson Disease after Automatic Mechanical Peripheral Stimulation: A Pilot Study.

Objective The present study shows the results of a double-blind sham-controlled pilot trial to test whether measurable stimulus-specific functional connectivity changes exist after Automatic Mechanical Peripheral Stimulation (AMPS) in patients with idiopathic Parkinson Disease. Methods Eleven patients (6 women and 5 men) with idiopathic Parkinson Disease underwent brain fMRI immediately before and after sham or effective AMPS. Resting state Functional Connectivity (RSFC) was assessed using the seed-ROI based analysis. Seed ROIs were positioned on basal ganglia, on primary sensory-motor cortices, on the supplementary motor areas and on the cerebellum. Individual differences for pre- and post-effective AMPS and pre- and post-sham condition were obtained and first entered in respective one-sample t-test analyses, to evaluate the mean effect of condition. Results Effective AMPS, but not sham stimulation, induced increase of RSFC of the sensory motor cortex, nucleus striatum and cerebellum. Secondly, individual differences for both conditions were entered into paired group t-test analysis to rule out sub-threshold effects of sham stimulation, which showed stronger connectivity of the striatum nucleus with the right lateral occipital cortex and the cuneal cortex (max Z score 3.12) and with the right anterior temporal lobe (max Z score 3.42) and of the cerebellum with the right lateral occipital cortex and the right cerebellar cortex (max Z score 3.79). Conclusions Our results suggest that effective AMPS acutely increases RSFC of brain regions involved in visuo-spatial and sensory-motor integration. Classification of Evidence This study provides Class II evidence that automatic mechanical peripheral stimulation is effective in modulating brain functional connectivity of patients with Parkinson Disease at rest. Trial Registration Clinical Trials.gov NCT01815281

Disembodied Mind: Cortical Changes Following Brainstem Injury in Patients with Locked-in Syndrome

Locked-in syndrome (LIS) following ventral brainstem damage is the most severe form of motor disability. Patients are completely entrapped in an unresponsive body despite consciousness is preserved. Although the main feature of LIS is this extreme motor impairment, minor non-motor dysfunctions such as motor imagery defects and impaired emotional recognition have been reported suggesting an alteration of embodied cognition, defined as the effects that the body and its performances may have on cognitive domains. We investigated the presence of structural cortical changes in LIS, which may account for the reported cognitive dysfunctions. For this aim, magnetic resonance imaging scans were acquired in 11 patients with LIS (6 males and 5 females; mean age: 52.3±5.2SD years; mean time interval from injury to evaluation: 9±1.2SD months) and 44 healthy control subjects matching patients for age, sex and education. Freesurfer software was used to process data and to estimate cortical volumes in LIS patients as compared to healthy subjects. Results showed a selective cortical volume loss in patients involving the superior frontal gyrus, the pars opercularis and the insular cortex in the left hemisphere, and the superior and medium frontal gyrus, the pars opercularis, the insular cortex, and the superior parietal lobule in the right hemisphere. As these structures are typically associated with the mirror neuron system, which represents the neural substrate for embodied simulation processes, our results provide neuroanatomical support for potential disembodiment in LIS.

Imaging of Renal Medullary Carcinoma

Renal medullary carcinoma (RMC) is a rare, highly aggressive tumor recognized as an independent pathological entity. African-descent adolescents and young adults with sickle cell hemoglobinopathy are the most affected groups. This rare subtype of renal cell carcinoma has its own morphogenetic and pathological characteristics. The major clinical manifestations include gross hematuria, abdominal or flank pain, and weight loss. The prognosis is very poor, with 95% of cases diagnosed at an advanced stage of the disease. In this review, we summarize the morphologic and dynamic characteristics of RMC under various imaging modalities such as ultrasound, computed tomography, and magnetic resonance. Differential diagnosis and management strategies are also discussed.

Increased alpha band functional connectivity following the quadrato motor training: A longitudinal study

Quadrato Motor Training (QMT) is a new training paradigm, which was found to increase cognitive flexibility, creativity and spatial cognition. In addition, QMT was reported to enhance inter- and intra-hemispheric alpha coherence as well as Fractional Anisotropy (FA) in a number of white matter pathways including corpus callosum. Taken together, these results seem to suggest that electrophysiological and structural changes induced by QMT may be due to an enhanced interplay and communication of the different brain areas within and between the right and the left hemisphere. In order to test this hypothesis using the exact low-resolution brain electromagnetic tomography (eLORETA), we estimated the current neural density and lagged linear connectivity (LLC) of the alpha band in the resting state electroencephalography (rsEEG) recorded with open (OE) and closed eyes (CE) at three different time points, following 6 and 12 weeks of daily QMT. Significant changes were observed for the functional connectivity. In particular, we found that limbic and fronto-temporal alpha connectivity in the OE condition increased after 6 weeks, while it enhanced at the CE condition in occipital network following 12-weeks of daily training. These findings seem to show that the QMT may have dissociable long-term effects on the functional connectivity depending on the different ways of recording rsEEG. OE recording pointed out a faster onset of Linear Lag Connectivity modulations that tend to decay as quickly, while CE recording showed sensible effect only after the complete 3-months training.

Bilateral remote cerebellar haemorrhage after spinal surgery: a case study and review of the literature.

Abstract Background: Remote cerebellar haemorrhage is a rare and unpredictable complication after intracranial and spinal surgery, although less frequently found in the latter. The physiopathology of this phenomenon has not been definitely explained. Objectives: To describe and discuss the potential implications and pathomechanism of a bilateral remote cerebellar haemorrhage case after spinal surgery and review the literature related to this rare phenomenon. Case report: A 75 year-old man developed bilateral remote cerebellar haemorrhage after a lumbar laminectomy. Brain CT and MRI examinations showed chronic bilateral remote cerebellar haemorrhage, right haemoventricle and bilateral supratentorial subarachnoid haemorrhage. Subsequently, the patient underwent rehabilitation therapy with improvement of symptoms. Conclusion: When large cerebrospinal fluid loss is observed during spinal surgery, brain imaging study should be carried out. The pathogenetic hypothesis of microcirculation vessels tearing, the role of previous spinal surgery and of cerebellar atrophy should be considered and validated with further investigation.

White Matter Microstructural Changes Following Quadrato Motor Training: A Longitudinal Study

Diffusion tensor imaging (DTI) is an important way to characterize white matter (WM) microstructural changes. While several cross-sectional DTI studies investigated possible links between mindfulness practices and WM, only few longitudinal investigations focused on the effects of these practices on WM architecture, behavioral change, and the relationship between them. To this aim, in the current study, we chose to conduct an unbiased tract-based spatial statistics (TBSS) analysis (n = 35 healthy participants) to identify longitudinal changes in WM diffusion parameters following 6 and 12 weeks of daily Quadrato Motor Training (QMT), a whole-body mindful movement practice aimed at improving well-being by enhancing attention, coordination, and creativity. We also investigated the possible relationship between training-induced WM changes and concomitant changes in creativity, self-efficacy, and motivation. Our results indicate that following 6 weeks of daily QMT, there was a bilateral increase of fractional anisotropy (FA) in tracts related to sensorimotor and cognitive functions, including the corticospinal tracts, anterior thalamic radiations, and uncinate fasciculi, as well as in the left inferior fronto-occipital, superior and inferior longitudinal fasciculi. Interestingly, significant FA increments were still present after 12 weeks of QMT in most of the above WM tracts, but only in the left hemisphere. FA increase was accompanied by a significant decrease of radial diffusivity (RD), supporting the leading role of myelination processes in training-related FA changes. Finally, significant correlations were found between training-induced diffusion changes and increased self-efficacy as well as creativity. Together, these findings suggest that QMT can improve WM integrity and support the existence of possible relationships between training-related WM microstructural changes and behavioral change.

Evaluating rehabilitation interventions in Parkinson's disease with functional MRI: a promising neuroprotective strategy

Parkinsons disease (PD) is a progressive neurodegenerative disorder affecting approximately 10 million people worldwide (Planetta et al., 2014; Zigmond and Smeyne, 2014). The principal clinical features of PD are bradykinesia, rigidity, tremor at rest and postural instability (Planetta et al., 2014). It is known that both PD itself and the use of anti-parkinson drugs are associated with several non-motor symptoms such as cognitive impairment, neuropsychiatric disturbances and sleep, autonomic, and sensory disorders (Park and Stacy, 2009; Foster et al., 2014). The histopathological hallmark of PD is the reduction of dopaminergic cells in the substantia nigra pars compacta, causing dopamine deficiency in specific nuclei of the basal ganglia such as the dorsal striatum (Fearnley and Lees, 1991; Planetta et al., 2014). The disruption of the dopaminergic system has long been regarded as the major cause of PD; however, it has been shown that a widespread involvement of several non-dopaminergic pathways also contribute to the clinical manifestations of PD (Park et al., 2014). Despite dopamine replacement therapy can improve some of the motor symptoms in most of PD patients for up to a decade, this therapy is poorly effective on cognitive function (Schapira et al., 2009; Zigmond and Smeyne, 2014). Currently, there are no treatment options able to significantly slow the progression of PD or reverse its neurodegenerative processes (Zigmond and Smeyne, 2014). Implementation of rehabilitation strategies might change the course of the disease; however, measures of brain changes after treatment should be used to quantify the effects and compare different protocols or approaches in clinical trials. Rehabilitation: The rehabilitation strategies in PD have been classified into three categories (Foster et al., 2014): (1) exercise or physical activity, (2) environmental cues, stimuli, and objects, and (3) self-management and cognitive-behavioral strategies. Exercise is emerging as an effective rehabilitation therapy in PD, especially for the motor symptoms (i.e., gait and balance) that are known to be associated with severe complications such as reduced mobility and increased risk of falls (Goodwin et al., 2008). Indeed, it has been shown that exercise might improve motor performance through a facilitation of both the cognitive and automatic control of movement and it might ameliorate cognition and emotional status (Petzinger et al., 2013; Zigmond and Smeyne, 2014). In recent years, several clinical trials have been launched to demonstrate the role of physical activity on reducing the risk of falls or improving UPDRS (Unified Parkinsons Disease Rating Scale) motor scores, balance or gait performance (Petzinger et al., 2013; Foster et al., 2014). For example, it has been shown in mild to moderate PD that aerobic walking exercise can improve motor function and fatigue together with mood, executive control and quality of life (Uc et al., 2014). Moreover, the practice of dance has been reported to be a short-term effective intervention that significantly improves the motor performance as compared with no intervention (Sharp and Hewitt, 2014). Clinical evidence has also shown that tai chi program performed consistently better than the resistance-training and stretching in maximum excursion of movements and in directional control in PD (Li et al., 2012). Physical exercise demonstrated its benefits not only in PD patients but also in other conditions involving CNS damage such as Alzheimers disease, amyotrophic lateral sclerosis, Huntingtons disease, spinal cord injury and stroke (Goodwin et al., 2008; Zigmond and Smeyne, 2014). There is a strong rationale behind the impact of physical exercise on neuroprotection in PD: it increases mitochondrial energy, stimulates antioxidant activity, reduces inflammation, causes angiogenesis and produces synaptogenesis (Zigmond and Smeyne, 2014). Recently published data suggest that exercise paradigms, including both goal-based practice and aerobic training, might work synergistically to promote neuroplasticity processes and improve the effects of aberrant circuitry within the basal ganglia in PD (Petzinger et al., 2013). Neuroplasticity is defined as the reorganization of neural networks in response to new experiences and changes in behaviour or environment, caused by brain encoding and learning (Kleim and Jones, 2008). Neuroplasticity is based on structural and physiological cellular mechanisms including synaptogenesis, neurogenesis, neuronal sprouting, and potentiation of synaptic strength (Sudhof and Malenka, 2008). The above mentioned exercise-induced changes on brain physiology might help to create a favorable environment for neuroplasticity in PD (Petzinger et al., 2013). In light of the multifaceted, heterogeneous and chronic nature of PD, patients would benefit from strategies that are adequately suited for the stage of disease and from interventions focused on physical performance skills and occupational performance through physical activity (Foster et al., 2014). fMRI: The role of structural imaging in PD is limited to support clinical findings in differentiating idiopathic PD from atypical or secondary parkinsonisms (Stoessl et al., 2014). MRI is the most commonly used method for non-invasively investigating the brain structure and function in vivo (Planetta et al., 2014; Stoessl et al., 2014). The contrast measured by means of functional MRI (fMRI) depends on blood oxygenation level-dependent (BOLD) signal that measures changes in relative amount of oxy/deoxyhaemoglobin under local hemodynamics changes induced by metabolic demands of neuronal activity (Planetta et al., 2014; Stoessl et al., 2014). BOLD changes can be used not only to measure task-dependent activity but also to assess temporal coherence of spatially segregated brain areas. Particularly brain activity can be assessed with fMRI data by calculating the temporal correlations of low-frequency spontaneous BOLD signal fluctuations between spatially distant regions in a rest condition (Stoessl et al., 2014). Abnormal resting state functional connectivity in PD has been recently demonstrated in brain networks studies (Stoessl et al., 2014). For instance, patients with PD showed decreased coupling in the cortico-striatal sensorimotor network and between the striatum and the brainstem and increased coupling in the associative network, possibly reflecting compensatory mechanisms (Helmich et al., 2010; Hacker et al., 2012). Moreover, in patients with tremor, an increased functional connectivity was reported between the internal globus pallidus, putamen and the cerebello-thalamic circuit, consistent with increased oscillatory electromyography (EMG) activity in these pathways (Helmich et al., 2011). Most importantly, the authors were also able to correlate MRI functional connectivity changes with EMG tremor activities leading them to conclude that resting tremor may be a consequence of pathological interactions between the basal ganglia and the cerebello-thalamic circuit (Helmich et al., 2011). The resting-state functional connectivity of motor circuits has been recently investigated using autoradiography in parkinsonian rats after long-term aerobic exercise, providing an interesting framework to explore the exercise-induced brain changes in PD (Wang et al., 2015). The authors showed that the effects of 4 weeks forced running wheel exercise in parkinsonian rodents included reintegration of the dorsolateral striatum into the motor network, emergence of the ventrolateral striatum as a network hub and increased resting-state functional connectivity among the motor cortex, motor thalamus, basal ganglia, and cerebellum (Wang et al., 2015). To date, the effects of rehabilitation and exercise have been poorly explored with fMRI in patients with PD. In particular, there is lack of knowledge about the neural correlates of the effects of either rehabilitation strategies or physical exercise alone or in combination, and their relationship with motor and non-motor symptoms in PD. Exploring the rehabilitation-induced brain functional connectivity changes and the effects on the clinical management of PD patients will lead to a better understanding of the undergoing neuroplasticity processes and potentially to the identification of novel disease-modifying interventions in PD. On this perspective, fMRI can be an extremely important tool, potentially able to explore the training-induced functional brain plasticity mechanisms and related neural networks in patients with PD as it has been already performed in healthy subjects (Taubert et al., 2011). It will be crucial to take into account the clinical eterogeneity of PD, ranging from akinetic-rigid to tremor dominant phenotypes (Zhang et al., 2015), the effect of disease compensatory mechanisms, medication, life style, diet or other confounding factors to avoid imaging analysis type II errors (Planetta et al., 2014; Stoessl et al., 2014). To sum up, the development of patient-tailored rehabilitation strategies for PD, taking into account motor and non-motor symptoms as well as psycho-physical and social environment will be a target of great interest in the following years. Quantitative functional MR imaging will play a crucial role to measure effectiveness of rehabilitation therapies in clinical trials and their effect on the dopaminergic pathological stream and its compensatory mechanisms.

Non-Uniform Distribution of Metastatic Intracranial Tumors in Cancer Patients

The risk of developing brain metastases (BMs) has been extensively estimated on the basis of clinicopathological properties of the primary tumor. An emerging paradigm is that tumors are able to produce factors that induce the formation of the so-called pre-metastatic niches in organs where metastases will ultimately develop. There is evidence of a preferential distribution of BMs in patients with breast cancer and lung cancer, confirmed by means of both autopsy and magnetic resonance imaging studies: e.g. breast cancer metastases are more frequent in the cerebellum and in the basal ganglia and non-small cell lung cancer metastases are preferentially distributed in the occipital lobe and in the cerebellum. The non-uniform distribution of brain metastases suggests the existence of mechanisms of brain-specific vulnerability/resistance to metastasis, yet to be deeply explored and understood, in the effort to modify and to increase efficacy of therapeutic approaches.