Loss of inhibition in sensorimotor networks in focal hand dystonia.

OBJECTIVE: To investigate GABA-ergic receptor density and associated brain functional and grey matter changes in focal hand dystonia (FHD). METHODS: 18 patients with FHD of the right hand and 18 age and gender matched healthy volunteers (HV) participated in this study. We measured the density of GABA-A receptors using [11C] Flumazenil and perfusion using [15O] H2O. Anatomical images were also used to measure grey matter volume with voxel-based morphometry (VBM). RESULTS: In FHD patients compared to HV, the vermis VI of the right cerebellum and the left sensorimotor cortex had a decrease of Flumazenil binding potential (FMZ-BP), whereas the striatum and the lateral cerebellum did not show significant change. Bilateral inferior prefrontal cortex had increased FMZ-BP and an increase of perfusion, which correlated negatively with disease duration. Only the left sensorimotor cortex showed a decrease of grey matter volume. INTERPRETATION: Impairments of GABAergic neurotransmission in the cerebellum and the sensorimotor cortical areas could explain different aspects of loss of inhibitory control in FHD, the former being involved in maladaptive plasticity, the latter in surround inhibition. Reorganization of the inferior prefrontal cortices, part of the associative network, might be compensatory for the loss of inhibitory control in sensorimotor circuits. These findings suggest that cerebellar and cerebral GABAergic abnormalities could play a role in the functional imbalance of striato-cerebello-cortical loops in dystonia.

The effect of daclizumab on brain atrophy in relapsing-remitting multiple sclerosis.

Daclizumab is a monoclonal antibody that reduces inflammation in multiple sclerosis (MS). Through a retrospective analysis, our objective was to determine whether daclizumab treatment reduces the rate of brain structure atrophy in comparison to a mixture of other disease-modifying therapies (mainly different interferon ß preparations). We analyzed MRI examinations (1332 scans from 70 MS cases) obtained between 2000 and 2011 in a single center and processed with an automated brain segmentation method. We used mixed-effects multivariable linear regression models to determine whether a median of 4.3 years of daclizumab therapy in 26 patients altered rates of brain-volume change, controlling for variations in MRI protocol. The control group consisted of 44 patients not treated with daclizumab. We found that supratentorial brain volume declined by 5.17 ml per year (95% confidence limits: 3.58-6.77) off daclizumab therapy. On daclizumab, the annual rate of volume loss decreased to 3.72 ml (p=0.01). The rate of ventricular enlargement decreased from 1.26 to 0.42 ml per year (p<0.001). Focused analysis suggests that reduction in gray matter atrophy rate most likely underlies these results. In summary, in this retrospective analysis, daclizumab therapy substantially decreased the rate of brain atrophy in relapsing-remitting MS in comparison to other disease-modifying therapies, predominantly interferon ß.

Anatomical correlates of blepharospasm.

BACKGROUND: Focal dystonia is a neurological disorder characterized by unwanted muscle spasms. Blepharospasm is a focal dystonia producing an involuntary closure of the eyelid. Its etiology is unknown. OBJECTIVE: To investigate if there are structural changes in the white and grey matter of blepharospasm patients, and if the changes are related to disease features. METHODS: T1 and diffusion-weighted magnetic resonance imaging scans were collected from 14 female blepharospasm patients and 14 healthy matched controls. Grey matter volumes, fractional anisotropy (FA), and mean diffusivity maps were compared between the groups. Based on grey matter differences within the facial portion of the primary motor cortex, the corticobulbar tract was traced and compared between groups. RESULTS: Changes in grey matter in patients included the facial portion of the sensorimotor area and anterior cingulate gyrus. These changes did not correlate with disease duration. Corticobulbar tract volume and peak tract connectivity were decreased in patients compared with controls. There were no significant differences in FA or mean diffusivity between groups. CONCLUSIONS: Grey matter changes within the primary sensorimotor and the anterior cingulate cortices in blepharospasm patients may help explain involuntary eyelid closure and the abnormal sensations often reported in this condition.

A magnetization transfer imaging study of corpus callosum myelination in young children with autism.

BACKGROUND: Several lines of evidence suggest that autism may be associated with abnormalities in white matter development. However, inconsistencies remain in the literature regarding the nature and extent of these abnormalities, partly because of the limited types of measurements that have been used. Here, we used magnetization transfer imaging to provide insight into the myelination of the corpus callosum in children with autism. METHODS: Magnetization transfer imaging scans were obtained in 101 children with autism and 35 typically developing children who did not significantly differ with regard to gender or age. The midsagittal area of the corpus callosum was manually traced and the magnetization transfer ratio (MTR) was calculated for each voxel within the corpus callosum. Mean MTR and height and location of the MTR histogram peak were analyzed. RESULTS: Mean MTR and MTR histogram peak height and location were significantly higher in children with autism than in typically developing children, suggesting abnormal myelination of the corpus callosum in autism. CONCLUSIONS: The differences in callosal myelination suggested by these results may reflect an alteration in the normally well-regulated process of myelination of the brain, with broad implications for neuropathology, diagnosis, and treatment of autism.

Evidence of left inferior frontal-premotor structural and functional connectivity deficits in adults who stutter.

The neurophysiological basis for stuttering may involve deficits that affect dynamic interactions among neural structures supporting fluid speech processing. Here, we examined functional and structural connectivity within corticocortical and thalamocortical loops in adults who stutter. For functional connectivity, we placed seeds in the left and right inferior frontal Brodmann area 44 (BA44) and in the ventral lateral nucleus (VLN) of the thalamus. Subject-specific seeds were based on peak activation voxels captured during speech and nonspeech tasks using functional magnetic resonance imaging. Psychophysiological interaction (PPI) was used to find brain regions with heightened functional connectivity with these cortical and subcortical seeds during speech and nonspeech tasks. Probabilistic tractography was used to track white matter tracts in each hemisphere using the same seeds. Both PPI and tractrography supported connectivity deficits between the left BA44 and the left premotor regions, while connectivity among homologous right hemisphere structures was significantly increased in the stuttering group. No functional connectivity differences between BA44 and auditory regions were found between groups. The functional connectivity results derived from the VLN seeds were less definitive and were not supported by the tractography results. Our data provide strongest support for deficient left hemisphere inferior frontal to premotor connectivity as a neural correlate of stuttering.

Similarities in speech and white matter characteristics in idiopathic developmental stuttering and adult-onset stuttering.

Adult-onset stuttering (AS) typically occurs following neurological and/or psychological trauma, considered different from developmental stuttering (DS), which starts during early childhood with few if any new cases reported after adolescence. Here we report four cases of AS, two with apparent psychological trigger and two without, none with evidence of neurological injury, and none conforming to previously reported characteristics of psychogenic stuttering. We asked whether this group of AS would have similar speech and neuroanatomical characteristics to those with DS. We conducted blinded analyses of speech samples in both AS cases and 14 cases of DS on type, frequency, and loci of disfluencies. Diffusion tensor imaging (DTI) was conducted to compare white matter tracts using fractional anisotropy (FA). We found that AS did not differ significantly from DS in any of the speech characteristics measured. On DTI, DS had significantly increased FA relative to controls in the right superior longitudinal tract. AS cases showed a similar trend for increases in these regions when compared to controls. The results of this study suggest that symptoms of idiopathic stuttering can begin during adulthood, and that similar neuroanatomical differences from controls may be associated with both developmental and adult onset idiopathic stuttering.

Functional but not structural networks of the human laryngeal motor cortex show left hemispheric lateralization during syllable but not breathing production.

The laryngeal motor cortex (LMC) is indispensible for the vocal motor control of speech and song production. Patients with bilateral lesions in this region are unable to speak and sing, although their nonverbal vocalizations, such as laughter and cry, are preserved. Despite the importance of the LMC in the control of voluntary voice production in humans, the literature describing its connections remains sparse. We used diffusion tensor probabilistic tractography and functional magnetic resonance imaging-based functional connectivity analysis to identify LMC networks controlling two tasks necessary for speech production: voluntary voice as repetition of two different syllables and voluntary breathing as controlled inspiration and expiration. Peaks of activation during all tasks were found in the bilateral ventral primary motor cortex in close proximity to each other. Functional networks of the LMC during voice production but not during controlled breathing showed significant left-hemispheric lateralization (p < 0.0005). However, structural networks of the LMC associated with both voluntary voice production and controlled breathing had bilateral hemispheric organization. Our findings indicate the presence of a common bilateral structural network of the LMC, upon which different functional networks are built to control various voluntary laryngeal tasks. Bilateral organization of functional LMC networks during controlled breathing supports its indispensible role in all types of laryngeal behaviors. Significant left-hemispheric lateralization of functional networks during simple but highly learned voice production suggests the readiness of the LMC network for production of a complex voluntary behavior, such as human speech.

Focal white matter changes in spasmodic dysphonia: a combined diffusion tensor imaging and neuropathological study.

Spasmodic dysphonia is a neurological disorder characterized by involuntary spasms in the laryngeal muscles during speech production. Although the clinical symptoms are well characterized, the pathophysiology of this voice disorder is unknown. We describe here, for the first time to our knowledge, disorder-specific brain abnormalities in these patients as determined by a combined approach of diffusion tensor imaging (DTI) and postmortem histopathology. We used DTI to identify brain changes and to target those brain regions for neuropathological examination. DTI showed right-sided decrease of fractional anisotropy in the genu of the internal capsule and bilateral increase of overall water diffusivity in the white matter along the corticobulbar/corticospinal tract in 20 spasmodic dysphonia patients compared to 20 healthy subjects. In addition, water diffusivity was bilaterally increased in the lentiform nucleus, ventral thalamus and cerebellar white and grey matter in the patients. These brain changes were substantiated with focal histopathological abnormalities presented as a loss of axonal density and myelin content in the right genu of the internal capsule and clusters of mineral depositions, containing calcium, phosphorus and iron, in the parenchyma and vessel walls of the posterior limb of the internal capsule, putamen, globus pallidus and cerebellum in the postmortem brain tissue from one patient compared to three controls. The specificity of these brain abnormalities is confirmed by their localization, limited only to the corticobulbar/corticospinal tract and its main input/output structures. We also found positive correlation between the diffusivity changes and clinical symptoms of spasmodic dysphonia (r = 0.509, P = 0.037). These brain abnormalities may alter the central control of voluntary voice production and, therefore, may underlie the pathophysiology of this disorder.

Comparison of methods for obtaining longitudinal whole-brain magnetization transfer measurements.

PURPOSE: To investigate whether the method of applying image masks can alter quantifiable measures determined from whole-brain MTR calculations. MATERIALS AND METHODS: Thirty-five T1/MT image pairs were obtained from five normal volunteers. For each pair a mask was used to specify the regions to be analyzed. Using these regions, a histogram was used to calculate seven global MTR metrics. This process was performed three ways: 1) using a unique mask for each T1/MT pair, 2) sharing a single mask for each subject and registering all intrasubject images to the image corresponding to their mask, and 3) sharing a single mask for each subject and transforming that mask into alignment with each of their original T1/MT image pairs. RESULTS: With respect to the first method, the latter two methods caused small but significant differences in several parameters. CONCLUSION: The method of applying image masks can affect whole-brain MTR values.