Neeraj Upadhyay

Functional connectivity changes and their relationship with clinical disability and white matter integrity in patients with relapsing–remitting multiple sclerosis

Background and objective: To define the pathological substrate underlying disability in multiple sclerosis by evaluating the relationship of resting-state functional connectivity with microstructural brain damage, as assessed by diffusion tensor imaging, and clinical impairments. Methods: Thirty relapsing–remitting patients and 24 controls underwent 3T-MRI; motor abilities were evaluated by using measures of walking speed, hand dexterity and balance capability, while information processing speed was evaluated by a paced auditory serial addiction task. Independent component analysis and tract-based spatial statistics were applied to RS-fMRI and diffusion tensor imaging data using FSL software. Group differences, after dual regression, and clinical correlations were modelled with General-Linear-Model and corrected for multiple comparisons. Results: Patients showed decreased functional connectivity in 5 of 11 resting-state-networks (cerebellar, executive-control, medial-visual, basal ganglia and sensorimotor), changes in inter-network correlations and widespread white matter microstructural damage. In multiple sclerosis, corpus callosum microstructural damage positively correlated with functional connectivity in cerebellar and auditory networks. Moreover, functional connectivity within the medial-visual network inversely correlated with information processing speed. White matter widespread microstructural damage inversely correlated with both the paced auditory serial addiction task and hand dexterity. Conclusions: Despite the within-network functional connectivity decrease and the widespread microstructural damage, the inter-network functional connectivity changes suggest a global brain functional rearrangement in multiple sclerosis. The correlation between functional connectivity alterations and callosal damage uncovers a link between functional and structural connectivity. Finally, functional connectivity abnormalities affect information processing speed rather than motor abilities.

Neuroimaging evidence of gray and white matter damage and clinical correlates in progressive supranuclear palsy

To evaluate gray matter (GM) and white matter (WM) abnormalities and their clinical correlates in patients with progressive supranuclear palsy (PSP). Sixteen PSP patients and sixteen age-matched healthy subjects underwent a clinical evaluation and multimodal magnetic resonance imaging, including three-dimensional T1-weighted imaging and diffusion tensor imaging (DTI). Volumetric and DTI analyses were computed using SPM and FSL tools. PSP patients showed GM volume decrease, involving the frontal cortex, putamen, pallidum, thalamus and accumbens nucleus, cerebellum, and brainstem. Additionally, they had widespread changes in WM bundles, mainly affecting cerebellar peduncles, thalamic radiations, corticospinal tracts, corpus callosum, and longitudinal fasciculi. GM volumes did not correlate with WM abnormalities. DTI indices of WM damage, but not GM volumes, correlated with clinical scores of disease severity and cognitive impairment. The neurodegenerative changes that occur in PSP involve both GM and WM structures and develop concurrently though independently. WM damage in PSP correlates with clinical scores of disease severity and cognitive impairment, thus providing further insight into the pathophysiology of the disease.

Dentate nucleus connectivity in adult patients with multiple sclerosis: functional changes at rest and correlation with clinical features

Background and objective: The dentate nucleus, which is the largest of the cerebellar nuclei, plays a critical role in movement and cognition. The aim of our study was to assess any changes in dentate functional connectivity (FC) in adult relapsing remitting multiple sclerosis (RR-MS) patients and to investigate possible clinical correlates. Materials and methods: In all, 54 patients and 24 healthy subjects (HS) underwent multimodal magnetic resonance imaging (MRI), including diffusion tensor imaging (DTI), three-dimensional-T1-weighted and resting state (RS) functional images; they also underwent a cognitive evaluation, that is, attention and information processing speed, by means of the Paced Auditory Serial Addition Test (PASAT). Patients were also scored according to Expanded Disability Status Scale (EDSS). RS-MRI data were analysed using FMRIB Software Library (FSL) tools, with the seed-based method to identify dentate FC. Results: When compared with HS, patients exhibited brain atrophy and widespread DTI abnormalities, as well as greater FC between the dentate nucleus and cortical areas, particularly in the frontal and parietal lobes. Within these areas, FC in patients correlated inversely with clinical impairment. Finally, FC correlated inversely with lesion load and microstructural brain damage. Conclusion: Our findings indicate that dentate FC at rest is altered in MS patients. Whether these functional changes are induced by the disease and play a compensatory role remains to be established.

Understanding the link between somatosensory temporal discrimination and movement execution in healthy subjects

The somatosensory temporal discrimination threshold (STDT) is the shortest interval at which an individual recognizes paired stimuli as separate in time. We investigated whether and how voluntary movement modulates STDT in healthy subjects. In 17 healthy participants, we tested STDT during voluntary index‐finger abductions at several time‐points after movement onset and during motor preparation. We then tested whether voluntary movement‐induced STDT changes were specific for the body segment moved, depended on movement kinematics, on the type of movement or on the intensity for delivering paired electrical stimuli for STDT. To understand the mechanisms underlying STDT modulation, we also tested STDT during motor imagery and after delivering repetitive transcranial magnetic stimulation to elicit excitability changes in the primary somatosensory cortex (S1). When tested on the moving hand at movement onset and up to 200 msec thereafter, STDT values increased from baseline, but during motor preparation remained unchanged. STDT values changed significantly during fast and slow index‐finger movements and also, though less, during passive index‐finger abductions, whereas during tonic index‐finger abductions they remained unchanged. STDT also remained unchanged when tested in body parts other than those engaged in movement and during imagined movement. Nor did testing STDT at increased intensity influence movement‐induced STDT changes. The cTBS‐induced S1 cortical changes left movement‐induced STDT changes unaffected. Our findings suggest that movement execution in healthy subjects may alter STDT processing.

Gray and white matter structural changes in corticobasal syndrome

We investigated gray matter and white matter (WM) changes in corticobasal syndrome (CBS). T1-weighted and diffusion tensor images (3T-magnet) were obtained in 11 patients and 11 healthy subjects (HS). Magnetic resonance imaging data were analyzed using FreeSurfer and Tracts Constrained by Underlying Anatomy to evaluate cortical thickness (CTh), surface area, and subcortical volumes as well as diffusion tensor image parameters along the major WM tracts. Compared with HS, the whole patient group showed decreased CTh in the prefrontal cortex, precentral gyrus, supplementary motor area, insula, and temporal pole bilaterally. When we divided patients into 2 subgroups (left: L-CBS, right: R-CBS) on the basis of the clinically more affected upper limb, the most prominent decrease in CTh occurred in the hemisphere contralateral to the more affected side. The whole patient group also had volume loss in the putamen, hippocampus, and accumbens bilaterally, in the corpus callosum and right amygdala. Finally, we found diffusion changes in several WM tracts with axial diffusivity being altered more than radial diffusivity. The upper limb motor severity negatively correlated with the contralateral CTh in the precentral and/or postcentral gyri and contralateral volumes of putamen and accumbens. The CTh asymmetry in postcentral and/or paracentral gyri also negatively correlated with disease duration. Cortical thinning, volume loss, and fiber tract degeneration in specific brain regions are important pathophysiological abnormalities in CBS.

MRI gray and white matter measures in progressive supranuclear palsy and corticobasal syndrome

We evaluated MRI measures of gray and white matter damages in 19 patients with progressive supranuclear palsy (PSP), 11 with corticobasal syndrome (CBS), and 14 healthy subjects (HS) to differentiate patients with PSP from those with CBS. We calculated surface-based maps of the cortical volume, cortical thickness, surface area, and voxel level maps of sub-cortical volume, and diffusion tensor imaging parameters using automated scripts implemented in FreeSurfer and FSL toolboxes. No significant differences in cortical volume loss were observed between PSP and CBS. When cortical volume was divided into cortical thickness and surface area, cortical thickness in peri-rolandic brain regions was significantly smaller in CBS than in PSP patients, whereas surface area was significantly smaller in PSP than HS. We also found widespread volume loss in sub-cortical structures in patients with PSP and CBS in comparison to HS. Both patient groups displayed diffusion tensor imaging abnormalities: compared to HS, widespread fractional anisotropy and radial diffusivity changes were observed in PSP, whereas axial and radial diffusivity changes were prominent in CBS. Mini-mental state examination positively correlated with diffusion changes in patients with PSP. In conclusion, cortical thickness, surface area, and diffusion tensor imaging parameters may be sensitive enough to help differentiate patients with PSP from those with CBS.

Temporal Dynamics of the Default Mode Network Characterize Meditation-Induced Alterations in Consciousness

Current research suggests that human consciousness is associated with complex, synchronous interactions between multiple cortical networks. In particular, the default mode network (DMN) of the resting brain is thought to be altered by changes in consciousness, including the meditative state. However, it remains unclear how meditation alters the fast and ever-changing dynamics of brain activity within this network. Here we addressed this question using simultaneous electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) to compare the spatial extents and temporal dynamics of the DMN during rest and meditation. Using fMRI, we identified key reductions in the posterior cingulate hub of the DMN, along with increases in right frontal and left temporal areas, in experienced meditators during rest and during meditation, in comparison to healthy controls (HCs). We employed the simultaneously recorded EEG data to identify the topographical microstate corresponding to activation of the DMN. Analysis of the temporal dynamics of this microstate revealed that the average duration and frequency of occurrence of DMN microstate was higher in meditators compared to HCs. Both these temporal parameters increased during meditation, reflecting the state effect of meditation. In particular, we found that the alteration in the duration of the DMN microstate when meditators entered the meditative state correlated negatively with their years of meditation experience. This reflected a trait effect of meditation, highlighting its role in producing durable changes in temporal dynamics of the DMN. Taken together, these findings shed new light on short and long-term consequences of meditation practice on this key brain network.

Neuroimaging correlates of blinking abnormalities in patients with progressive supranuclear palsy

We aimed to identify the possible relationship between blinking abnormalities and neuroimaging changes in patients with progressive supranuclear palsy.

Abnormal motor cortex excitability during linguistic tasks in adductor-type spasmodic dysphonia

In healthy subjects (HS), transcranial magnetic stimulation (TMS) applied during ‘linguistic’ tasks discloses excitability changes in the dominant hemisphere primary motor cortex (M1). We investigated ‘linguistic’ task‐related cortical excitability modulation in patients with adductor‐type spasmodic dysphonia (ASD), a speech‐related focal dystonia. We studied 10 ASD patients and 10 HS. Speech examination included voice cepstral analysis. We investigated the dominant/non‐dominant M1 excitability at baseline, during ‘linguistic’ (reading aloud/silent reading/producing simple phonation) and ‘non‐linguistic’ tasks (looking at non‐letter strings/producing oral movements). Motor evoked potentials (MEPs) were recorded from the contralateral hand muscles. We measured the cortical silent period (CSP) length and tested MEPs in HS and patients performing the ‘linguistic’ tasks with different voice intensities. We also examined MEPs in HS and ASD during hand‐related ‘action‐verb’ observation. Patients were studied under and not‐under botulinum neurotoxin‐type A (BoNT‐A). In HS, TMS over the dominant M1 elicited larger MEPs during ‘reading aloud’ than during the other ‘linguistic’/‘non‐linguistic’ tasks. Conversely, in ASD, TMS over the dominant M1 elicited increased‐amplitude MEPs during ‘reading aloud’ and ‘syllabic phonation’ tasks. CSP length was shorter in ASD than in HS and remained unchanged in both groups performing ‘linguistic’/‘non‐linguistic’ tasks. In HS and ASD, ‘linguistic’ task‐related excitability changes were present regardless of the different voice intensities. During hand‐related ‘action‐verb’ observation, MEPs decreased in HS, whereas in ASD they increased. In ASD, BoNT‐A improved speech, as demonstrated by cepstral analysis and restored the TMS abnormalities. ASD reflects dominant hemisphere excitability changes related to ‘linguistic’ tasks; BoNT‐A returns these excitability changes to normal.

Freezing of gait in Parkinson’s disease: gray and white matter abnormalities

Freezing of gait (FOG) is a disabling disorder that often affects Parkinson’s disease (PD) patients in advanced stages of the disease. To study structural gray matter (GM) and white matter (WM) changes in PD patients with and without FOG, twenty-one PD patients with FOG (PD-FOG), 16 PD patients without FOG (PD-nFOG) and 19 healthy subjects (HS) underwent a standardized MRI protocol. For the gray matter evaluation, cortical volume (CV), cortical thickness (CTh), and surface area (SA) were analyzed using the FreeSurfer pipeline. For the white matter evaluation, DTI images were analyzed using tracts constrained by underlying anatomy (TRACULA) toolbox in FreeSurfer. PD-FOG patients exhibited lower CTh than HS in the mesial surface of both cerebral hemispheres, including the superior frontal gyrus, paracentral lobule, posterior cingulate cortex, precuneus and pericalcarine cortex, and in the right dorsolateral prefrontal cortex. Moreover, significant WM changes were observed in PD-FOG patients in comparison with HS in the superior longitudinal fasciculus, uncinate fasciculus, cingulum cingulate gyrus and inferior longitudinal fasciculus (prevalently in the right hemisphere) and in the frontal radiations of the corpus callosum. DTI abnormalities in specific WM bundles correlated significantly with cognitive measures. The damage of multiple cortical areas involved in high-level gait control together with WM disruption between motor, cognitive and limbic structures may represent the anatomical correlate of FOG.