Chiara Mastropasqua

Theta Burst Stimulation Modulates Cerebellar-Cortical Connectivity in Patients with Progressive Supranuclear Palsy

BACKGROUND Progressive Supranuclear Palsy (PSP) is an atypical degenerative Parkinsonism characterized by postural instability, supranuclear gaze palsy and frontal deficits. Recent imaging studies revealed that the volume of cerebellar peduncles and midbrain were reduced in PSP. Transcranial magnetic stimulation (TMS) studies demonstrated a cerebellar involvement in PSP showing an impairment of functional connectivity between the cerebellar hemisphere (Cb) and the contralateral primary motor cortex (M1) (cerebellar brain inhibition-CBI). OBJECTIVE To investigate the plasticity of the cerebello-thalamo-cortical circuits in ten PSP patients after two-week course of cerebellar intermittent theta burst stimulation (iTBS), a form of repetitive TMS. METHODS Before and after the iTBS sessions we measured functional connectivity between Cb and contralateral M1 (CBI), short intracortical inhibition (SICI) and intracortical facilitation (ICF) and short latency afferent inhibition (SLAI) in contralateral M1. We also performed resting state functional magnetic resonance (rs-fMRI) and we administered clinical rating scale (PSP-RS). RESULTS At baseline PSP patients had decreased efficiency of CBI, SICI and SLAI in comparison to PD patients and healthy subjects. Cerebellar iTBS increased the deficient functional cerebellar-motor connectivity as assessed by CBI. No effect was seen for SICI/ICF and SLAI circuits. Following iTBS there was an increased signal in the head of the caudate nucleus bilaterally as shown by rs-fMRI. Moreover, PSP-RS showed an improvement of dysarthria in all patients. CONCLUSIONS iTBS enhanced functional connectivity between the cerebellar hemisphere, the caudate nucleus and the cortex, that was paralleled by some clinical improvement. Future randomized, sham-stimulation controlled studies are warranted to support the clinical efficacy of this technique.

Abnormal Functional Brain Connectivity and Personality Traits in Myotonic Dystrophy Type 1

IMPORTANCE Myotonic dystrophy type 1 (DM1), the most common muscular dystrophy observed in adults, is a genetic multisystem disorder affecting several other organs besides skeletal muscle, including the brain. Cognitive and personality abnormalities have been reported; however, no studies have investigated brain functional networks and their relationship with personality traits/disorders in patients with DM1. OBJECTIVE To use resting-state functional magnetic resonance imaging to assess the potential relationship between personality traits/disorders and changes to functional connectivity within the default mode network (DMN) in patients with DM1. DESIGN, SETTING, AND PARTICIPANTS We enrolled 27 patients with genetically confirmed DM1 and 16 matched healthy control individuals. Patients underwent personality assessment using clinical interview and Minnesota Multiphasic Personality Inventory-2 administration; all participants underwent resting-state functional magnetic resonance imaging. Investigations were conducted at the Istituto di Ricovero e Cura a Carattere Scientifico Santa Lucia Foundation, Catholic University of Sacred Heart, and Azienda Ospedaliera San Camillo Forlanini. INTERVENTION Resting-state functional magnetic resonance imaging. MAIN OUTCOMES AND MEASURES Measures of personality traits in patients and changes in functional connectivity within the DMN in patients and controls. Changes in functional connectivity and atypical personality traits in patients were correlated. RESULTS We combined results obtained from the Minnesota Multiphasic Personality Inventory-2 and clinical interview to identify a continuum of atypical personality profiles ranging from schizotypal personality traits to paranoid personality disorder within our DM1 patients. We also demonstrated an increase in functional connectivity in the bilateral posterior cingulate and left parietal DMN nodes in DM1 patients compared with controls. Moreover, patients with DM1 showed strong associations between DMN functional connectivity and schizotypal-paranoid traits. CONCLUSIONS AND RELEVANCE Our findings provide novel biological evidence that DM1 is a clinical condition that also involves an alteration of functional connectivity of the brain. We speculate that these functional brain abnormalities, similarly to frank psychiatric disorders, may account for the atypical personality traits observed in patients with DM1.

Theta burst stimulation improves visuo-spatial attention in a patient with traumatic brain injury

Recent studies showed that non-invasive brain stimulation methods, such as repetitive transcranial magnetic stimulation (rTMS) can improve the symptoms of neglect in stroke patients. Here, we adopted this approach to improve visuo-spatial deficit in a patient with traumatic brain injury (TBI) that showed important symptoms of visuo-spatial neglect. We found that continuous theta burst stimulation (cTBS) applied over the left posterior parietal cortex (PPC) induced a clinical improvement of cognitive disorder associated to a functional changes of fronto-parietal network as assessed by means of TMS and resting state fMRI.

Longitudinal Changes in Functional Brain Connectivity Predicts Conversion to Alzheimer’s Disease

This longitudinal study investigates the modifications in structure and function occurring to typical Alzheimers disease (AD) brains over a 2-year follow-up, from pre-dementia stages of disease, with the aim of identifying biomarkers of prognostic value. Thirty-one patients with amnestic mild cognitive impairment were recruited and followed-up with clinical, neuropsychological, and MRI assessments. Patients were retrospectively classified as AD Converters or Non-Converters, and the data compared between groups. Cross-sectional MRI data at baseline, assessing volume and functional connectivity abnormalities, confirmed previous findings, showing a more severe pattern of regional grey matter atrophy and default-mode network disconnection in Converters than in Non-Converters. Longitudinally, Converters showed more grey matter atrophy in the frontotemporal areas, accompanied by increased connectivity in the precuneus. Discriminant analysis revealed that functional connectivity of the precuneus within the default mode network at baseline is the parameter able to correctly classify patients in Converters and Non-Converters with high sensitivity, specificity, and accuracy.

Resting-State Functional Connectivity Changes Between Dentate Nucleus and Cortical Social Brain Regions in Autism Spectrum Disorders

Autism spectrum disorders (ASDs) are known to be characterized by restricted and repetitive behaviors and interests and by impairments in social communication and interactions mainly including “theory of mind” (ToM) processes. The cerebellum has emerged as one of the brain regions affected by ASDs. As the cerebellum is known to influence cerebral cortex activity via cerebello-thalamo-cortical (CTC) circuits, it has been proposed that cerebello-cortical “disconnection” could in part underlie autistic symptoms. We used resting-state (RS) functional magnetic resonance imaging (fMRI) to investigate the potential RS connectivity changes between the cerebellar dentate nucleus (DN) and the CTC circuit targets, that may contribute to ASD pathophysiology. When comparing ASD patients to controls, we found decreased connectivity between the left DN and cerebral regions known to be components of the ToM network and the default mode network, implicated in specific aspects of mentalizing, social cognition processing, and higher order emotional processes. Further, a pattern of overconnectivity was also detected between the left DN and the supramodal cerebellar lobules associated with the default mode network. The presented RS-fMRI data provide evidence that functional connectivity (FC) between the dentate nucleus and the cerebral cortex is altered in ASD patients. This suggests that the dysfunction reported within the cerebral cortical network, typically related to social features of ASDs, may be at least partially related to an impaired interaction between cerebellum and key cortical social brain regions.

TMS evidence for a selective role of the precuneus in source memory retrieval

The posteromedial cortex including the precuneus (PC) is thought to be involved in episodic memory retrieval. Here we used continuous theta burst stimulation (cTBS) to disentangle the role of the precuneus in the recognition memory process in a sample of healthy subjects. During the encoding phase, subjects were presented with a series of colored pictures. Afterwards, during the retrieval phase, all previously presented items and a sample of new pictures were presented in black, and subjects were asked to indicate whether each item was new or old, and in the latter case to indicate the associated color. cTBS was delivered over PC, posterior parietal cortex (PPC) and vertex before the retrieval phase. The data were analyzed in terms of hits, false alarms, source errors and omissions. cTBS over the precuneus, but not over the PPC or the vertex, induced a selective decrease in source memory errors, indicating an improvement in context retrieval. All the other accuracy measurements were unchanged. These findings suggest a direct implication of the precuneus in successful context-dependent retrieval.

Widespread alterations in functional brain network architecture in amnestic mild cognitive impairment

We investigated changes in functional network architecture in amnestic mild cognitive impairment using graph-based analysis of task-free functional magnetic resonance imaging and fine cortical parcellation. Widespread disconnection was observed primarily in cortical hubs known to manifest early Alzheimers disease pathology, namely precuneus, parietal lobules, supramarginal and angular gyri, and cuneus, with additional involvement of subcortical regions, sensorimotor cortex and insula. The connectivity changes determined using graph-based analysis significantly exceed those detected using independent component analysis both in amplitude and topographical extent, and are largely decoupled from the presence of overt atrophy. This superior ability of graph-based analysis to detect disease-related disconnection highlights its potential use in the determination of biomarkers of early dementia. Graph-based analysis source code is provided as supplementary material.

Functional Anatomy of the Thalamus as a Model of Integrated Structural and Functional Connectivity of the Human Brain In Vivo

Abstract While methods of measuring non-invasively both, functional and structural brain connectivity are available, the degree of overlap between them is still unknown. In this paper this issue is addressed by investigating the connectivity pattern of a brain structure with many, well characterized structural connections, namely the thalamus. Diffusion-weighted and resting state (RS) functional MRI (fMRI) data were collected in a group of 38 healthy participants. Probabilistic tractography was performed to parcellate the thalamus into regions structurally connected to different cortical areas. The resulting regions were used as seeds for seed-based analysis of RS fMRI data. The tractographic parcellation was thus cross-validated against functional connectivity data by evaluating the overlap between the functional and structural thalamo-cortical connections originating from the parcellated regions. Our data show only a partial overall correspondence between structural and functional connections, in the same group of healthy individuals, thus suggesting that the two approaches provide complementary and not overlapping information. Future studies are warranted to extend the results we obtained in the thalamus to other structures, and to confirm that the mechanisms behind functional connectivity are more complex than just expressing structural connectivity.

Network based statistical analysis detects changes induced by continuous theta-burst stimulation on brain activity at rest

We combined continuous theta-burst stimulation (cTBS) and resting state (RS)-fMRI approaches to investigate changes in functional connectivity (FC) induced by right dorsolateral prefrontal cortex (DLPFC)–cTBS at rest in a group of healthy subjects. Seed-based fMRI analysis revealed a specific pattern of correlation between the right prefrontal cortex and several brain regions: based on these results, we defined a 29-node network to assess changes in each network connection before and after, respectively, DLPFC–cTBS and sham sessions. A decrease of correlation between the right prefrontal cortex and right parietal cortex (Brodmann areas 46 and 40, respectively) was detected after cTBS, while no significant result was found when analyzing sham-session data. To our knowledge, this is the first study that demonstrates within-subject changes in FC induced by cTBS applied on prefrontal area. The possibility to induce selective changes in a specific region without interfering with functionally correlated area could have several implications for the study of functional properties of the brain, and for the emerging therapeutic strategies based on transcranial stimulation.

High-resolution, graph-based analysis reveals pervasive functional disconnection in mild cognitive impairment

pre-scan diagnosis was 84.3% for PIB and 82.1% for FDG. The primary diagnosis was changed after PET in 13/140 patients (9.3%): 12/13 changes were concordant with PIB and 8/13 with FDG results. When examined independently, both discordant PIB and discordant FDG were associated with a change in diagnosis (p<0.0001). However, multivariate analysis revealed that changes in diagnosis were associated with discordant PIB (p1⁄40.00013) but not discordant FDG (p1⁄40.087) (LRadditional covariates: clinical dilemmas pre -PET, gender, age at PET, baseline diagnosis, new patient (follow up before PET of less than 1 year) and CDR <1) 35% of patients had a change in AD therapy post-PET (initiating or discontinuing acetycholinesterase inhibitors or memantine). In the entire population changes in treatment were not associated with discordant PIB or discordant FDG (p>0.05 in LR model); however discordant PIB did affect treatment in of patients with non-Ab pre-PET diagnoses (p1⁄40.028), driven by the initiation of acetycholinesterase inhibitors in patients who were unexpectedly PIB-positive. Conclusions: Overall concordance of PET amyloid and FDG results with clinical diagnosis was high and changes in diagnosis were uncommon. Discordant PIB had a greater effect on diagnostic changes than discordant FDG. Impact on treatment was more modest than on diagnosis and limited to Ab negative patients.