Characterization of white matter alterations using diffusion kurtosis imaging in patients with amyotrophic lateral sclerosis.

BACKGROUND: To evaluate the degeneration of the corticospinal tract (CST) and corpus callosum (CC) in patients with motor neuron disease and upper motor neuron (UMN) dysfunction using diffusion kurtosis imaging (DKI). METHODS: Twenty-seven patients and 33 healthy controls underwent magnetic resonance imaging along with clinical and neuropsychological testing. Tractography of diffusion tensor images was performed to extract tracts of the bilateral CST and CC. Group mean differences both across the entire averaged tract and along each tract were assessed, including correlations between diffusion metrics and clinical measures. Tract-based spatial statistics (TBSS) was performed to evaluate the spatial distribution of whole-brain microstructural abnormalities in patients. RESULTS: In comparison to controls, patients had significantly higher mean and radial diffusivity and lower fractional anisotropy (FA), kurtosis anisotropy, mean kurtosis (MK), and radial kurtosis (RK) in the CST and CC (p < .017). Along-the-tract analysis revealed changes concentrated in the posterior limb of the internal capsule, corona radiata, and primary motor cortex (false-discovery rate p < .05). FA of the left CST correlated with disease progression rate, whereas MK of the bilateral CST correlated with UMN burden (p < .01). TBSS results corroborated along-tract analysis findings and additionally revealed reduced RK and MK in the fornix, where diffusion tensor imaging (DTI) changes were absent. CONCLUSION: DKI abnormalities in the CST and CC are present in patients with UMN dysfunction, potentially revealing complementary information to DTI regarding the pathology and microstructural alterations occurring in such patients. DKI shows promise as a potential in vivo biomarker for cerebral degeneration in amyotrophic lateral sclerosis.

White matter alterations in drug-naïve children with Tourette syndrome and obsessive-compulsive disorder.

Tourette syndrome (TS) and early-onset obsessive-compulsive disorder (OCD) are frequently associated and conceptualized as distinct phenotypes of a common disease spectrum. However, the nature of their relationship is still largely unknown on a pathophysiological level. In this study, early structural white matter (WM) changes investigated through diffusion tensor imaging (DTI) were compared across four groups of drug-naïve children: TS-pure (n = 16), TS+OCD (n = 14), OCD (n = 10), and 11 age-matched controls. We analyzed five WM tracts of interest, i.e., cortico-spinal tract (CST), anterior thalamic radiations (ATR), inferior longitudinal fasciculus (ILF), corpus callosum (CC), and cingulum and evaluated correlations of DTI changes to symptom severity. Compared to controls, TS-pure and TS+OCD showed a comparable pattern of increased fractional anisotropy (FA) in CST, ATR, ILF and CC, with FA changes displaying negative correlation to tic severity. Conversely, in OCD, FA decreased in all WM tracts (except for the cingulum) compared to controls and negatively correlated to symptoms. We demonstrate different early WM microstructural alterations in children with TS-pure/TS+OCD as opposed to OCD. Our findings support the conceptualization of TS+OCD as a subtype of TS while suggesting that OCD is characterized by independent pathophysiological mechanisms affecting WM development.

Functional alterations in large-scale resting-state networks of amyotrophic lateral sclerosis: A multi-site study across Canada and the United States.

Amyotrophic lateral sclerosis (ALS) is a multisystem neurodegenerative disorder characterized by progressive degeneration of upper motor neurons and lower motor neurons, and frontotemporal regions resulting in impaired bulbar, limb, and cognitive function. Magnetic resonance imaging studies have reported cortical and subcortical brain involvement in the pathophysiology of ALS. The present study investigates the functional integrity of resting-state networks (RSNs) and their importance in ALS. Intra- and inter-network resting-state functional connectivity (Rs-FC) was examined using an independent component analysis approach in a large multi-center cohort. A total of 235 subjects (120 ALS patients; 115 healthy controls (HC) were recruited across North America through the Canadian ALS Neuroimaging Consortium (CALSNIC). Intra-network and inter-network Rs-FC was evaluated by the FSL-MELODIC and FSLNets software packages. As compared to HC, ALS patients displayed higher intra-network Rs-FC in the sensorimotor, default mode, right and left fronto-parietal, and orbitofrontal RSNs, and in previously undescribed networks including auditory, dorsal attention, basal ganglia, medial temporal, ventral streams, and cerebellum which negatively correlated with disease severity. Furthermore, ALS patients displayed higher inter-network Rs-FC between the orbitofrontal and basal ganglia RSNs which negatively correlated with cognitive impairment. In summary, in ALS there is an increase in intra- and inter-network functional connectivity of RSNs underpinning both motor and cognitive impairment. Moreover, the large multi-center CALSNIC dataset permitted the exploration of RSNs in unprecedented detail, revealing previously undescribed network involvement in ALS.

DREZotomy in the management of post brachial plexus root avulsion neuropathic pain: fMRI correlates for pain relief.

BACKGROUND: Deafferentiation pain following brachial plexus root avulsion has been documented to be severe enough to affect activities of daily living in patients. Microsurgical DREZotomy is known to alleviate the symptoms by decreasing the afferent signals transmitted from the spinal cord to sensory cortex. OBJECTIVES: To document and analyse the effectiveness of DREZotomy and to evaluate the role of 'sensory cortex' in the cause and relief of dysesthetic pain, using fMRI. MATERIALS AND METHODS: This was a prospective study conducted between 2010 and 2016 and included all patients who underwent DREZotomy for dysesthetic pain following traumatic brachial plexus injury (TBPI). Patients were evaluated both preoperatively and postoperatively with Visual Analogue Scale(VAS), Hospital Anxiety and Depression score (HADS) and SF36 questionnaire and effectiveness of surgery was assessed. Functional magnetic resonance imaging (fMRI) of the brain in resting state was performed before and after surgery and was also compared with controls. Patients underwent standard microsurgical DREZotomy from C5 to D1. Postoperative assessment was done at 6 weeks and 6 months following surgery. RESULTS: Our series had 18 patients aged between 22 and 63 years. RTA was the most common cause of injury. There was significant decrease in pain at 6 months follow up compared to pre-operative values as assessed by VAS, HADS, SF36 questionnaire. fMRI analysis revealed cluster activations in the sensory, motor cortex and in the right cingulate gyrus in the preoperative group which was higher than in normal controls. In the postoperative group, the size of the resting state activation was significantly reduced. CONCLUSION: DREZotomy is an effective procedure for TBPI patients. We hypothesize that these fMRI findings reflect the cortical reorganization that occurs not only after injury but also following successful surgery which explains the cause and relief of dyesthetic pain.

Resting-state functional connectivity of anterior and posterior cerebellar lobes is altered in multiple sclerosis.

BACKGROUND: Damage to the cerebellar sensorimotor and cognitive domains may underlie physical and cognitive disability. OBJECTIVE: To investigate resting-state functional connectivity (FC) of sensorimotor and cognitive cerebellum, and clinical correlates in multiple sclerosis (MS). METHODS: A total of 119 patients with MS and 42 healthy subjects underwent multimodal 3T-magnetic resonance imaging (MRI). Patients were evaluated using the Expanded Disability Status Scale and Multiple Sclerosis Functional Composite Scale. After parcellation of sensorimotor (lobules I-V + VIII) and cognitive cerebellum (lobules VI, VII, IX, X), we calculated cerebellar resting-state FC using a seed-based approach. RESULTS: In patients with MS, the sensorimotor cerebellum showed increased FC mainly with cerebellar, thalamic, and cortical (frontal, parietal, temporal) areas and decreased FC with insular areas; the cognitive cerebellum showed increased FC mainly with thalamic and cortical (temporal-occipital) areas, and decreased FC with frontal-insular areas. Both sensorimotor and cognitive cerebellar FC negatively correlated with disability, and positively with cognitive scores. Cerebellar structural damage only partially influenced results. CONCLUSION: The two neocerebellar circuits showed altered FC with subcortical and cortical areas. The association between increased sensorimotor and cognitive cerebellar FC and low levels of physical and cognitive disability suggests that altered FC might modulate the effects of cerebellar structural damage on clinical condition.

Involvement of the dentate nucleus in the pathophysiology of amyotrophic lateral sclerosis: A multi-center and multi-modal neuroimaging study.

Amyotrophic lateral sclerosis (ALS) is characterized primarily by motor neuron but also frontotemporal lobar degeneration. Although the cerebellum is involved in both motor and cognitive functions, little is known of its role in ALS. We targeted the dentate nucleus (DN) in the cerebellum and the associated white matter fibers tracts connecting the DN to the rest of the brain using multimodal imaging techniques to examine the cerebellar structural and functional connectivity patterns in ALS patients and hypothesized that the DN is implicated in the pathophysiology of ALS. A cohort of 127 participants (56 healthy subjects (HS); 71 ALS patients) were recruited across Canada through the Canadian ALS Neuroimaging Consortium (CALSNIC). Resting state functional MRI, diffusion tensor imaging (DTI), and 3D weighted T1 structural images were acquired on a 3-tesla scanner. The DN in the cerebellum was used as a seed to evaluate the whole brain cerebral resting-state functional connectivity (rsFC). The superior cerebellar peduncle (SCP), middle cerebellar peduncle (MCP) and inferior cerebellar peduncle (ICP) were used as a region of interest in DTI to evaluate the structural integrity of the DN with the cortex and brain stem. Cerebellar volumetric analysis was done to examine the lobular and DN grey matter (GM) changes in ALS patients. Lastly, an association between DN rsFC and structural alterations were explored. DN rsFC was reduced with cerebrum (supplementary motor area, precentral gyrus, frontal, posterior parietal, temporal), lobule IV, and brain stem, and increased with parieto-occipital region. DN rsFC and white matter (WM) diffusivity alterations at SCP, MCP, and ICP were accompanied by correlations with ALSFRS-R. There were no DN volumetric changes. Notably, DN rsFC correlated with WM abnormalities at superior cerebellar peduncle. The DN plays a pathophysiological role in ALS. Impaired rsFC is likely due to the observed cerebellar peduncular WM damage given the lack of GM atrophy of the DN. This study demonstrates altered cerebellar rsFC connectivity with motor and extra-motor regions in ALS, and impaired rsFC is likely due to the observed cerebellar peduncular WM damage given the lack of GM atrophy of the DN. The correlation between the altered DN connectivity, and the behavioral data support the hypothesis that the DN plays a pathophysiological role in ALS.

A Comprehensive Approach to Disentangle the Effect of Cerebellar Damage on Physical Disability in Multiple Sclerosis.

Cerebellar damage occurs frequently in multiple sclerosis (MS) patients, with a wide exhibition of symptoms particularly as impairments of balance and gait. Recent studies implementing new postprocessing magnetic resonance imaging (MRI) techniques showed how cerebellar subregional atrophy provides an explanation of disability in MS. The aim of this work was to evaluate the relationship between quantitative measures of physical disability, cerebellar subregional atrophy, and cerebellar peduncle disruption. Forty-nine MS patients and 32 healthy subjects as controls (HS) underwent a 3-Tesla MRI including 3D T1-weighted and diffusion tensor imaging. Patients underwent static posturography to calculate the body's center of pressure (COP) displacement, Expanded Disability Status Scale (EDSS), and 25-ft walking test (25-FWT). Cerebellar lobular volumes were automatically calculated using the Spatially Unbiased Infratentorial Toolbox. Tract-based spatial statistics (TBSS) in FSL was used to process diffusion tensor imaging (DTI) Fit-generated fractional anisotropy (FA) maps to assess structural connectivity of cerebellar peduncles. Stepwise multivariate linear regression analyses were used to explore relationships between variables. Cerebellar volumes (anterior and posterior, as well as lobular volumes from I to X) were significantly lower in patients with MS than HS (p < 0.05). FA in all cerebellar peduncles was lower in MS patients than in HS (p < 0.05). EDSS and 25-FWT showed an association with atrophy of lobule VIIIb (ß = -0.37, p < 0.01, and ß = -0.45, p < 0.001, respectively) COP measures inversely correlated with volume of lobules I-IV (ß = -0.37, p < 0.01, and ß = -0.36, p < 0.01). Lower FA in the three cerebellar peduncles of MS patients positively correlated with cerebellar lobular volumes. Our findings show how sensorimotor cerebellum atrophy and disruption of both afferent and efferent cerebellar connections contribute to physical disability in MS patients.

Functional disconnection of the dentate nucleus in essential tremor.

Despite previous functional MRI studies on alterations within the cerebello-thalamo-cortical circuit in patients with essential tremor (ET), the specific role of disconnection of the dentate nucleus (DN), the main output cerebellar pathway, still needs clarification. In this study, we evaluated DN functional connectivity (FC) changes and their relationship with motor and non-motor symptoms in ET. We studied 25 ET patients and 26 healthy controls. Tremor severity was assessed using the Fahn-Tolosa-Marin tremor rating scale (FTM-TRS) and tremor amplitude and frequency were evaluated using kinematic techniques. Cognitive profile was assessed by montreal cognitive assessment (MoCA) and frontal assessment battery (FAB). All participants underwent a 3 T MRI protocol including resting-state blood oxygenation level dependent and diffusion tensor sequences. We used a seed-based approach to investigate DN FC and to explore the diffusion properties of cerebellar peduncles. There was significantly decreased DN FC with cortical, subcortical, and cerebellar areas in ET patients compared with healthy controls. Correlation analysis showed that: (1) the DN FC with the supplementary motor area, pre and postcentral gyri, and prefrontal cortex negatively correlated with FTM-TRS score and disease duration; (2) DN FC changes in the thalamus and caudate negatively correlated with peak tremor frequency, changes in the cerebellum positively correlated with tremor amplitude, and changes in the bilateral thalamus negatively correlated with tremor amplitude, and (3) DN FC with the associative prefrontal and parietal cortices, basal ganglia, and thalamus positively correlated with the MoCA score. Diffusion abnormalities were found in the three cerebellar peduncles, which did not correlate with clinical scores.

Aberrant functional connectivity in patients with Parkinson's disease and freezing of gait: a within- and between-network analysis.

Freezing of gait (FOG) is a disabling motor symptom that affects patients with Parkinson's disease (PD). MRI-based evidence suggest that multiple brain structures are involved in the occurrence of FOG. We investigated the integrity of the neuronal networks in PD patients with FOG (PD-FOG), considering both within-network resting-state functional connectivity (rsFC) and between-network rsFC. Thirty-one PD patients (15 PD-FOG and 16 PD-nFOG) and 16 healthy subjects (HS) underwent a rsfMRI study. The data was analysed by using FSL Melodic and FSLNets software to study within- and between-network rsFC. PD-FOG displayed a higher within-network rsFC that involved a greater number of resting-state networks (RSNs) than PD-nFOG. rsFC in the basal ganglia network significantly correlated with the Timed Up and Go test. Moreover, when compared with HS, PD-FOG displayed reduced rsFC between the right fronto-parietal and executive-control RSNs, which significantly correlated with FOG severity. This study demonstrates that FOG is associated with an impaired interplay and communication between the RSNs that underpin attentive and executive abilities, especially in the right hemisphere.

Neuroimaging advances in Parkinson's disease with freezing of gait: A systematic review.

Freezing of gait (FOG) is a paroxysmal gait disorder that often occurs at advanced stages of Parkinson's disease (PD). FOG consists of abrupt walking interruption and severe difficulty in locomotion with an increased risk of falling. Pathophysiological mechanisms underpinning FOG in PD are still unclear. However, advanced MRI and nuclear medicine studies have gained relevant insights into the pathophysiology of FOG in PD. Neuroimaging studies have demonstrated structural and functional abnormalities in a number of cortical and subcortical brain regions in PD patients with FOG. In this paper, we systematically review existing neuroimaging literature on the structural and functional brain changes described in PD patients with FOG, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We evaluate previous studies using various MRI techniques to estimate grey matter loss and white matter degeneration. Moreover, we review functional brain changes by examining functional MRI and nuclear medicine imaging studies. The current review provides up-to-date knowledge in this field and summarizes the possible mechanisms responsible for FOG in PD.

White matter rather than gray matter damage characterizes essential tremor.

OBJECTIVES: We investigated changes in gray matter (GM) and white matter (WM) in the whole brain, including both cortical and subcortical structures, and their relationship with tremor severity, psychiatric symptoms, and cognitive impairment in patients affected by essential tremor (ET). METHODS: We studied 19 ET patients and 15 healthy subjects (HS). All the subjects underwent a 3-T MRI study based on 3D-T1 and diffusion tensor images. For the GM analysis, cortical thickness was assessed by using the Computational Anatomy Tool, basal ganglia and thalamus volumes by using the FMRIB software library, and cerebellum lobular volumes by using the spatial unbiased atlas template. For the WM assessment, we performed a voxel-wise analysis by means of tract-based spatial statistics. Patients' tremor severity and psychiatric and cognitive disorders were evaluated by means of standard clinical scales. Neuroimaging data were correlated with clinical scores. RESULTS: We found significantly smaller right and left thalamic volumes in ET patients than in HS, which correlated with cognitive scores. We did not observe any significant differences either in cortical thickness or in cerebellar lobular volumes between patients and HS. WM abnormalities were detected in most hemisphere bundles, particularly in the corticospinal tract, cerebellar peduncles, and corpus callosum. The WM abnormalities significantly correlated with tremor severity, cognitive profile, and depression. CONCLUSION: Our study indicates that ET is characterized by several GM and WM changes of both infra- and supratentorial brain structures. The results may help to better understand mechanisms underlying tremor severity and psychiatric and cognitive impairment in ET. KEY POINTS: • We performed a comprehensive evaluation of gray and white matter in the same sample of patients with essential tremor using recently developed data analysis methods. • Essential tremor is characterized by widespread gray and white matter changes in both infra- and supratentorial brain structures. The results may help to better understand motor and non-motor symptoms in patients with essential tremor.

Abnormal Cerebellar Connectivity Patterns in Patients with Parkinson's Disease and Freezing of Gait.

In this study, we aimed to evaluate the importance of cerebellum in freezing of gait (FOG) pathophysiology. Due to the fundamental role of the cerebellum in posture and gait control, we examined cerebellar structural and functional connectivity (FC) in patients with PD and FOG. We recruited 15 PD with FOG (PD-FOG), 16 PD without FOG (PD-nFOG) patients, and 16 healthy subjects (HS). The FOG Questionnaire (FOG-Q) assessed FOG severity. Three tesla-MRI study included resting-state functional MRI, diffusion tensor imaging (DTI), and 3D T1-w images. We located seed regions in the cerebellar locomotor region, fastigial, and dentate nucleus to evaluate their FC. DTI parameters were obtained on the superior, middle, and inferior cerebellar peduncles. Global and lobular cerebellum volumes were also calculated. Cerebellar locomotor and fastigial FC was higher in cerebellar and posterior cortical areas in PD-FOG than in HS. FC of the cerebellar locomotor region with cerebellar areas positively correlated with FOG-Q. Dentate FC was lower in the prefrontal and parieto-occipital cortices in PD-FOG than in HS and in the brainstem, right basal ganglia, and frontal and parieto-occipital cortices than in PD-nFOG. DTI parameters in superior and middle cerebellar peduncles were altered in PD-FOG compared with PD-nFOG and significantly correlated with FOG-Q. There were no differences in cerebellar volumes between PD-FOG and either PD-nFOG or HS. Our results suggest that altered connectivity of the cerebellum contributes to the pathophysiology of FOG. FC of the cerebellar locomotor region and white matter (WM) properties of cerebellar peduncles correlate with FOG severity, supporting the hypothesis that abnormal cerebellar function underlies FOG in PD.

Abnormal Resting-State Functional Connectivity in Progressive Supranuclear Palsy and Corticobasal Syndrome.

BACKGROUND: Pathological and MRI-based evidence suggests that multiple brain structures are likely to be involved in functional disconnection between brain areas. Few studies have investigated resting-state functional connectivity (rsFC) in progressive supranuclear palsy (PSP) and corticobasal syndrome (CBS). In this study, we investigated within- and between-network rsFC abnormalities in these two conditions. METHODS: Twenty patients with PSP, 11 patients with CBS, and 16 healthy subjects (HS) underwent a resting-state fMRI study. Resting-state networks (RSNs) were extracted to evaluate within- and between-network rsFC using the Melodic and FSLNets software packages. RESULTS: Increased within-network rsFC was observed in both PSP and CBS patients, with a larger number of RSNs being involved in CBS. Within-network cerebellar rsFC positively correlated with mini-mental state examination scores in patients with PSP. Compared to healthy volunteers, PSP and CBS patients exhibit reduced functional connectivity between the lateral visual and auditory RSNs, with PSP patients additionally showing lower functional connectivity between the cerebellar and insular RSNs. Moreover, rsFC between the salience and executive-control RSNs was increased in patients with CBS compared to HS. CONCLUSION: This study provides evidence of functional brain reorganization in both PSP and CBS. Increased within-network rsFC could represent a higher degree of synchronization in damaged brain areas, while between-network rsFC abnormalities may mainly reflect degeneration of long-range white matter fibers.

Cortical plasticity after brachial plexus injury and repair: a resting-state functional MRI study.

OBJECTIVE The authors aimed to understand the alterations of brain resting-state networks (RSNs) in patients with pan-brachial plexus injury (BPI) before and after surgery, which might provide insight into cortical plasticity after peripheral nerve injury and regeneration. METHODS Thirty-five patients with left pan-BPI before surgery, 30 patients after surgery, and 25 healthy controls underwent resting-state functional MRI (rs-fMRI). The 30 postoperative patients were subdivided into 2 groups: 14 patients with improvement in muscle power and 16 patients with no improvement in muscle power after surgery. RSNs were extracted using independent component analysis to evaluate connectivity at a significance level of p < 0.05 (familywise error corrected). RESULTS The patients with BPI had lower connectivity in their sensorimotor network (SMN) and salience network (SN) and greater connectivity in their default mode network (DMN) before surgery than the controls. Connectivity of the left supplementary motor cortex in the SMN and medial frontal gyrus and in the anterior cingulate cortex in the SN increased in patients whose muscle power had improved after surgery, whereas no significant changes were noted in the unimproved patients. There was a trend toward reduction in DMN connectivity in all the patients after surgery compared with that in the preoperative patients; however, this result was not statistically significant. CONCLUSIONS The results of this study highlight the fact that peripheral nerve injury, its management, and successful treatment cause dynamic changes within the brain's RSNs, which includes not only the obvious SMN but also the higher cognitive networks such as the SN and DMN, which indicates brain plasticity and compensatory mechanisms at work.

Spectrum of renal disorders in a tertiary care hospital in Haryana.

INTRODUCTION: There is a paucity of data pertaining to spectrum of renal diseases in various parts of India. Available literature has emphasized more on specific clinical syndromes of renal diseases rather than over all spectrum. The present study highlights specimen of symptomatic renal disorders at a tertiary care hospital in Haryana and will find place for better resource management and planning. MATERIALS AND METHODS: It included 1806 patients either presenting for the first time to nephrology outpatient department of admitted between Jan 1996 - Dec 2001 to the institute. The study was retrospective for five years (1996-2000) and prospective for one year. Records of all these patients were analyzed and patients were grouped in different renal syndromes. RESULTS: Mean age of patients was (38.79 +/- 15.15 years) with male preponderance in all renal syndromes. Chronic renal failure (CRF) was the commonest presentation (56.02%). Nephrotic syndrome accounted for 22.36% whereas acute renal failure (ARF) was seen in 12.84%. Other presentations were acute nephritic syndrome (6.75%) and asymptomatic urinary abnormality (AUA) (0.99%). Chronic glomerulonephritis (CGN) (39.32%) and diabetic nephropathy (DN) (19.16%) were leading causes of CRF. Medical ARF accounted for 2/3rd of the cases of ARF and surgical etiology was seen in 1/5th of causes whereas obstetric cause was responsible for 1/7th of the cases. Minimal change disease (MCD) (33.33%) was the commonest cause of primary nephrotic syndrome followed by membranoproliferative glomeruolonephritis (MPGN). Secondary glomerular diseases were found in 21.28%. Post-streptococcal glomerulonephritis (PSGN) was the commonest cause of nephritic syndrome (37.70%). CONCLUSION: It is the first large study of its kind from a tertiary health care centre of Haryana. Male patients in their peak of life (3rd and 4th decade) were the major candidates requiring renal care with CRF as the commonest presentation and diabetic nephropathy as the second commonest cause of CRF after CGN. We need more Indian studies on spectrum of renal diseases for better available resource management.

Organophosphate induced delayed neuropathy.

A 19 year young male who consumed organophosphorous compound and required assisted mechanical ventilation for two weeks, later on developed delayed neuropathy is described.