Cerebellar Agenesis and Bilateral Polimicrogyria Associated with Rare Variants of CUB and Sushi Multiple Domains 1 Gene (CSMD1): A Longitudinal Neuropsychological and Neuroradiological Case Study.

Cerebellar agenesis is an extremely rare condition characterized by a near complete absence of the cerebellum. The pathogenesis and molecular basis remain mostly unknown. We report the neuroradiological, molecular, neuropsychological and behavioral characterization of a 5-year-old girl, with cerebellar agenesis associated with parietal and peri-Sylvian polymicrogyria, followed-up for 10 years at four time points. Whole exome sequencing identified two rare variants in CSMD1, a gene associated with neurocognitive and psychiatric alterations. Mild intellectual impairment, cerebellar ataxia and deficits in language, memory and executive functions, with relatively preserved adaptive and psychopathological domains, were initially showed. Phonological awareness and verbal memory declined at 11 years of age, and social and anxiety problems emerged. Adaptive and psychopathological characteristics dramatically worsened at 15 years. In summary, the developmental clinical outcome showed impairment in multiple cognitive functions in childhood, with a progressive decline in cognitive and adaptive abilities and the emergence of psychopathological symptoms in adolescence. The observed phenotype could be the result of a complex interplay between cerebellar abnormality, brain malformation and the relations with CSMD1 variants. These findings may provide insights into the developmental clinical outcomes of a co-occurrence between rare brain malformation and rare genetic variants associated to neurodevelopmental disorders.

Superficial white matter damage in anti-NMDA receptor encephalitis.

BACKGROUND: Clinical brain MRI is normal in the majority of patients with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. However, extensive deep white matter damage wasrecently identifiedin these patients using diffusion weighted imaging. Here, our aim was to study a particularly vulnerable brain compartment, the late myelinating superficial white matter. METHODS: Forty-six patients with anti-NMDAR encephalitis were included. Ten out of these were considered neurologically recovered (modified Rankin scale of zero), while 36 patients were non-recovered. In addition, 30 healthy controls were studied. MRI data were collected from all subjects and superficial white matter mean diffusivity derived from diffusion tensor imaging was compared between groups in whole brain, lobar and vertex-based analyses. Patients underwent comprehensive cognitive testing, and correlation analyses were performed between cognitive performance and superficial white matter integrity. RESULTS: Non-recovered patients showed widespread superficial white matter damage in comparison to recovered patients and healthy controls. Vertex-based analyses revealed that damage predominated in frontal and temporal lobes. In contrast, the superficial white matter was intact in recovered patients. Importantly, persistent cognitive impairments in working memory, verbal memory, visuospatial memory and attention significantly correlated with damage of the superficial white matter in patients. CONCLUSIONS: Anti-NMDAR encephalitis is associated with extensive superficial white matter damage in patients with incomplete recovery. The strong association with impairment in several cognitive domains highlights the clinical relevance of white matter damage in this disorder and warrants investigations of the underlying pathophysiological mechanisms.

White Matter Sexual Dimorphism of the Adult Human Brain.

Sex-biased psychophysiology, behavior, brain function, and conditions are extensive, yet underlying structural brain mechanisms remain unclear. There is contradicting evidence regarding sexual dimorphism when it comes to brain structure, and there is still no consensus on whether or not there exists such a dimorphism for brain white matter. Therefore, we conducted a voxel-based morphometry (VBM) analysis along with global volume analysis for white matter across sex. We analyzed 384 T1-weighted MRI brain images (192 male, 192 female) to investigate any differences in white matter (WM) between males and females. In the VBM analysis, we found males to have larger WM, compared to females, in occipital, temporal, insular, parietal, and frontal brain regions. In contrast, females showed only one WM region to be significantly larger than males: the right postcentral gyrus in the parietal lobe region. Although, on average, males showed larger global WM volume, we did not find any significant difference in global WM volume between males and females.

Major Superficial White Matter Abnormalities in Huntington's Disease.

BACKGROUND: The late myelinating superficial white matter at the juncture of the cortical gray and white matter comprising the intracortical myelin and short-range association fibers has not received attention in Huntington's disease. It is an area of the brain that is late myelinating and is sensitive to both normal aging and neurodegenerative disease effects. Therefore, it may be sensitive to Huntington's disease processes. METHODS: Structural MRI data from 25 Pre-symptomatic subjects, 24 Huntington's disease patients and 49 healthy controls was run through a cortical pattern-matching program. The surface corresponding to the white matter directly below the cortical gray matter was then extracted. Individual subject's Diffusion Tensor Imaging (DTI) data was aligned to their structural MRI data. Diffusivity values along the white matter surface were then sampled at each vertex point. DTI measures with high spatial resolution across the superficial white matter surface were then analyzed with the General Linear Model to test for the effects of disease. RESULTS: There was an overall increase in the axial and radial diffusivity across much of the superficial white matter (p < 0.001) in Pre-symptomatic subjects compared to controls. In Huntington's disease patients increased diffusivity covered essentially the whole brain (p < 0.001). Changes are correlated with genotype (CAG repeat number) and disease burden (p < 0.001). CONCLUSIONS: This study showed broad abnormalities in superficial white matter even before symptoms are present in Huntington's disease. Since, the superficial white matter has a unique microstructure and function these abnormalities suggest it plays an important role in the disease.

The superficial white matter in Alzheimer's disease.

White matter abnormalities have been shown in the large deep fibers of Alzheimer's disease patients. However, the late myelinating superficial white matter comprised of intracortical myelin and short-range association fibers has not received much attention. To investigate this area, we extracted a surface corresponding to the superficial white matter beneath the cortex and then applied a cortical pattern-matching approach which allowed us to register and subsequently sample diffusivity along thousands of points at the interface between the gray matter and white matter in 44 patients with Alzheimer's disease (Age: 71.02 ± 5.84, 16M/28F) and 47 healthy controls (Age 69.23 ± 4.45, 19M/28F). In patients we found an overall increase in the axial and radial diffusivity across most of the superficial white matter (P < 0.001) with increases in diffusivity of more than 20% in the bilateral parahippocampal regions and the temporal and frontal lobes. Furthermore, diffusivity correlated with the cognitive deficits measured by the Mini-Mental State Examination scores (P < 0.001). The superficial white matter has a unique microstructure and is critical for the integration of multimodal information during brain maturation and aging. Here we show that there are major abnormalities in patients and the deterioration of these fibers relates to clinical symptoms in Alzheimer's disease.

Recollection and familiarity components of recognition: effect of side of mesio-temporal damage.

We investigated the memory performance of three patients with unilateral mesio-temporal lobe damage with the aim of evaluating the roles of the left and right hemispheres in recollection and familiarity. Consistent with the "Material Specificity Hypothesis", the right brain-damaged individual was selectively poor on recollection and familiarity tests for faces. Conversely, left-lesioned patients were severely deficient in recollection and familiarity of verbal material but mildly deficient on visual-spatial tests. This partially unexpected finding is interpreted in light of the ability of humans to verbally recode almost any material, thus giving rise to left-hemisphere effects for nominally nonverbal stimuli.

Corpus Callosum Structure is Topographically Correlated with the Early Course of Cognition and Depression in Alzheimer's Disease.

Corpus callosum (CC) abnormalities may cause cognitive and neuropsychiatric complications due to reduced hemispheric integration. Over a one-year period, we investigated whether the CC structure of 20 patients with mild Alzheimer's disease (AD) was linked to the evolution of cognitive and neuropsychiatric symptoms. We also investigated whether this anatomical-clinical relationship was localized topographically on the CC by combining voxel-based morphometry and diffusion tensor imaging approaches. We assessed patients' global cognitive deterioration and neuropsychiatric symptoms with the Mini-Mental State Examination and the Neuropsychiatric Inventory. Increased global cognitive deterioration during the early course of AD was significantly related to reduced white matter density (p = 0.004) and fractional anisotropy (FA) (p = 0.012) and increased mean diffusivity (MD) (p = 0.017) at the level of the CC isthmus/splenium. Further, increased depression severity was significantly related to reduced FA (p = 0.008) and increased MD (p = 0.018) at the level of the CC rostrum. These results indicate that changes in early myelinated CC fibers, which subserve the lateral temporal and parietal cortices and are less vulnerable to damage, may be related to cognitive impairment. Furthermore, changes in late myelinated CC fibers, which connect the orbitofrontal cortices and are more vulnerable to damage, may be related to the earliest neuropsychiatric symptoms of AD, such as depression.

The role of iron in gray matter degeneration in Huntington's disease: a magnetic resonance imaging study.

In Huntington's disease, iron accumulation in basal ganglia accompanies neuronal loss. However, if iron content changes with disease progression and how it relates to gray matter atrophy is not clear yet. We explored iron content in basal ganglia and cortex and its relationship with gray matter volume in 77 mutation carriers [19 presymptomatic, 8 with soft symptoms (SS), and 50 early-stage patients) and 73 matched-controls by T2*relaxometry and T1-weighted imaging on a 3T scanner. The ANCOVA model showed that iron accumulates in the caudate in presymptomatic subjects (P = 0.004) and remains relatively stable along disease stages in this nucleus; while increases in putamen and globus pallidus (P < 0.05). Volume instead decreases in basal ganglia, starting from the caudate (P < 0.0001) and extending to the putamen and globus pallidus (P ≤ 0.001). The longer the disease duration and the higher the CAG repeats, the higher the iron accumulation and the smaller the volume. In the cortex, iron decreases in parieto-occipital areas in SS (P < 0.027); extending to premotor and parieto-temporo-occipital areas in patients (P < 0.003); while volume declines in frontoparietal and temporal areas in presymptomatic (P < 0.023) and SS (P < 0.045), and extends throughout the cortex, with the exception of anterior frontal regions, in patients (P < 0.023). There is an inverse correlation between volume and iron levels in putamen, globus pallidus and the anterior cingulate; and a direct correlation in cortical structures (SMA-sensoriomotor and temporo-occipital). Iron homeostasis is affected in the disease; however, there appear to be differences in the role played by iron in basal ganglia and in cortex.

Selective Cognitive Dysfunction Is Related to a Specific Pattern of Cerebral Damage in Persons With Severe Traumatic Brain Injury.

OBJECTIVE: Cognitive dysfunction is a common sequela of traumatic brain injury (TBI); indeed, patients show a heterogeneous pattern of cognitive deficits. This study was aimed at investigating whether patients who show selective cognitive dysfunction after TBI present a selective pattern of cerebral damage. SETTING: Post-Coma Unit, IRCCS Santa Lucia Foundation, Rome, Italy. PARTICIPANTS: We collected data from 8 TBI patients with episodic memory disorder and without executive deficits, 7 patients with executive function impairment and preserved episodic memory capacities, and 16 healthy controls. DESIGN: We used 2 complementary analyses: (1) an exploratory and qualitative approach in which we investigated the distribution of lesions in the TBI groups, and (2) a hypothesis-driven and quantitative approach in which we calculated the volume of hippocampi of individuals in the TBI and control groups. MAIN MEASURES: Neuropsychological scores and hippocampal volumes. RESULTS: We found that patients with TBI and executive functions impairment presented focal lesions involving the frontal lobes, whereas patients with TBI and episodic memory disorders showed atrophic changes of the mesial temporal structure (hippocampus). CONCLUSION: The complexity of TBI is due to several heterogeneous factors. Indeed, studying patients with TBI and selective cognitive dysfunction should lead to a better understanding of correlations with specific brain impairment and damage, better follow-up of long-term outcome scenarios, and better planning of selective and focused rehabilitation programs.

Deep white matter in Huntington's disease.

White matter (WM) abnormalities have already been shown in presymptomatic (Pre-HD) and symptomatic HD subjects using Magnetic Resonance Imaging (MRI). In the present study, we examined the microstructure of the long-range large deep WM tracts by applying two different MRI approaches: Diffusion Tensor Imaging (DTI) -based tractography, and T2*weighted (iron sensitive) imaging. We collected Pre-HD subjects (n = 25), HD patients (n = 25) and healthy control subjects (n = 50). Results revealed increased axial (AD) and radial diffusivity (RD) and iron levels in Pre-HD subjects compared to controls. Fractional anisotropy decreased between the Pre-HD and HD phase and AD/RD increased and although impairment was pervasive in HD, degeneration occurred in a pattern in Pre-HD. Furthermore, iron levels dropped for HD patients. As increased iron levels are associated with remyelination, the data suggests that Pre-HD subjects attempt to repair damaged deep WM years before symptoms occur but this process fails with disease progression.

Prospective memory impairment and executive dysfunction in prefrontal lobe damaged patients: is there a causal relationship?

BACKGROUND: The prospective memory (PM) construct is aimed at capturing cognitive operations involved in the successful accomplishment of delayed intentions. It is generally agreed that PM impairment occurs in patients with prefrontal lobes damage. OBJECTIVE: To evaluate if there is a causal role of a deficit of executive abilities (failures of planning, set-shifting, selective attention, or working memory) over the PM impairment. METHODS: We report a detailed investigation of PM and executive abilities in two patients with posttraumatic damage to prefrontal lobes who complained from a reduced compliance with appointments and daily routines. RESULTS: Laboratory tests confirmed a difficulty in fulfilling delayed intentions in response to the occurrence of critical events and elapsed time. In one patient, PM impairment was associated with poor performance on tests investigating planning, working memory, and mental shifting. The other patient performed in the normal range on all executive tests. CONCLUSIONS: Despite the frequent claim of a dependence of PM deficits from executive dysfunction, the reported cases demonstrate that this is not necessarily the case. The results are discussed in the light of current hypotheses relating PM impairment to other deficits that commonly occur as a result of damage to the prefrontal lobes.

Tractography of the corpus callosum in Huntington's disease.

White matter abnormalities have been shown in presymptomatic and symptomatic Huntington's disease (HD) subjects using Magnetic Resonance Imaging (MRI) and Diffusion Tensor Imaging (DTI) methods. The largest white matter tract, the corpus callosum (CC), has been shown to be particularly vulnerable; however, little work has been done to investigate the regional specificity of tract abnormalities in the CC. Thus, this study examined the major callosal tracts by applying DTI-based tractography. Using TrackVis, a previously defined region of interest tractography method parcellating CC into seven major tracts based on target region was applied to 30 direction DTI data collected from 100 subjects: presymptomatic HD (Pre-HD) subjects (n=25), HD patients (n=25) and healthy control subjects (n=50). Tractography results showed decreased fractional anisotropy (FA) and increased radial diffusivity (RD) across broad regions of the CC in Pre-HD subjects. Similar though more severe deficits were seen in HD patients. In Pre-HD and HD, callosal FA and RD were correlated with Disease Burden/CAG repeat length as well as motor (UHDRSI) and cognitive (URDRS2) assessments. These results add evidence that CC pathways are compromised prior to disease onset with possible demyelination occurring early in the disease and suggest that CAG repeat length is a contributing factor to connectivity deficits. Furthermore, disruption of these callosal pathways potentially contributes to the disturbances of motor and cognitive processing that characterize HD.

Bihemispheric stimulation over left and right inferior frontal region enhances recovery from apraxia of speech in chronic aphasia.

Several studies have already shown that transcranial direct current stimulation (tDCS) is a useful tool for enhancing recovery in aphasia. However, all tDCS studies have previously investigated the effects using unihemisperic stimulation. No reports to date have examined the role of bihemispheric tDCS on aphasia recovery. Here, eight aphasic persons with apraxia of speech underwent intensive language therapy in two different conditions: real bihemispheric anodic ipsilesional stimulation over the left Broca's area and cathodic contralesional stimulation over the right homologue of Broca's area, and a sham condition. In both conditions, patients underwent concurrent language therapy for their apraxia of speech. The language treatment lasted 10 days (Monday to Friday, then weekend off, then Monday to Friday). There was a 14-day intersession interval between the real and the sham conditions. In all patients, language measures were collected before (T0), at the end of (T10) and 1 week after the end of (F/U) treatment. Results showed that after simultaneous excitatory stimulation to the left frontal hemisphere and inhibitory stimulation to the right frontal hemisphere regions, patients exhibited a significant recovery not only in terms of better accuracy and speed in articulating the treated stimuli but also in other language tasks (picture description, noun and verb naming, word repetition, word reading) which persisted in the follow-up session. Taken together, these data suggest that bihemispheric anodic ipsilesional and cathodic contralesional stimulation in chronic aphasia patients may affect the treated function, resulting in a positive influence on different language tasks.

tDCS stimulation segregates words in the brain: evidence from aphasia.

A number of studies have already shown that modulating cortical activity by means of transcranial direct current stimulation (tDCS) improves noun or verb naming in aphasic patients. However, it is not yet clear whether these effects are equally obtained through stimulation over the frontal or the temporal regions. In the present study, the same group of aphasic subjects participated in two randomized double-blind experiments involving two intensive language treatments for their noun and verb retrieval difficulties. During each training, each subject was treated with tDCS (20 min, 1 mA) over the left hemisphere in three different conditions: anodic tDCS over the temporal areas, anodic tDCS over the frontal areas, and sham stimulation, while they performed a noun and an action naming tasks. Each experimental condition was run in five consecutive daily sessions over three weeks with 6 days of intersession interval. The order of administration of the two language trainings was randomly assigned to all patients. Overall, with respect to the other two conditions, results showed a significant greater improvement in noun naming after stimulation over the temporal region, while verb naming recovered significantly better after stimulation of the frontal region. These improvements persisted at one month after the end of each treatment suggesting a long-term effect on recovery of the patients' noun and verb difficulties. These data clearly suggest that the mechanisms of recovery for naming can be segregated coupling tDCS with an intensive language training.

Cerebellar vermis abnormalities and cognitive functions in individuals with Williams syndrome.

In Williams syndrome (WS) cerebellar measures were only indirectly related to behavioral outcomes. T1-weighted magnetic resonance images and neuropsychological data were acquired to investigate whether cerebellar vermis differences were present in 12 WS individuals compared with 13 chronological age-matched controls and whether WS cerebellar vermis measures were related to cognitive scores. In WS participants, we observed a significant increase in the volume of the posterior superior cerebellar vermis (lobules VI-VII) and an atypical ratio between width and height of the cerebellar vermis. Furthermore, we found an inverse correlation between cerebellar posterior vermis volume and scores on implicit learning, phonological fluency and the verbal short-term memory tasks. The present study supported a role for the posterior cerebellar vermis in higher cognitive processes and indicated that the cerebellar vermis abnormalities (enlargement) in WS individuals have an effect in worsening the cognitive performance in specific domains.

Prolonged rock climbing activity induces structural changes in cerebellum and parietal lobe.

This article analyzes whether climbing, a motor activity featured by upward movements by using both feet and hands, generation of new strategies of motor control, maintenance of not stable equilibrium and adoption of long-lasting quadrupedal posture, is able to modify specific brain areas. MRI data of 10 word-class mountain climbers (MC) and 10 age-matched controls, with no climbing experience were acquired. Combining region-of-interest analyses and voxel-based morphometry we investigated cerebellar volumes and correlation between cerebellum and whole cerebral gray matter. In comparison to controls, world-class MC showed significantly larger vermian lobules I-V volumes, with no significant difference in other cerebellar vermian lobules or hemispheres. The cerebellar enlargement was associated with an enlargement of right medial posterior parietal area. The specific features of the motor climbing skills perfectly fit with the plastic anatomical changes we found. The enlargement of the vermian lobules I-V seems to be related to highly dexterous hand movements and to eye-hand coordination in the detection of and correction of visuomotor errors. The concomitant enlargement of the parietal area is related to parallel work in predicting sensory consequences of action to make movement corrections. Motor control and sensory-motor prediction of actions make the difference between survive or not at extreme altitude.

Differential involvement of the left frontal and temporal regions in verb naming: a tDCS treatment study.

PURPOSE: In aphasic patients, some studies have already emphasized the efficacy of transcranial direct current stimulation (tDCS) during the treatment of noun retrieval deficits. To date, in the same population, there are have been no studies addressing tDCS effects in the recovery of verb retrieval deficits. In this study, we wanted to test the potential of tDCS to improve verb production in a group of aphasic patients. METHODS: Seven chronic subjects participated in an intensive language training for their difficulties in action naming. Each subject was treated with tDCS (20 min., 1 mA) over the left hemisphere in three different conditions: anodic tDCS over Wernicke's area, anodic tDCS and sham stimulation over Broca's area. Each experimental condition was performed in five consecutive daily sessions over three weeks with 6 days of intersession interval. RESULTS: In all patients, results showed a significantly better response accuracy during the anodic tDCS over Broca's area with respect to the other two conditions which still persisted at one month after the end of the treatment suggesting a long-term effect on the recovery of their verb retrieval deficits. CONCLUSION: These findings further confirm that tDCS represents a useful new therapeutic interventions for the rehabilitation of lexical deficits in aphasic patients.

Memory and anatomical change in severe non missile traumatic brain injury: ∼1 vs. ∼8 years follow-up.

In previous studies, we investigated a group of subjects who had suffered from a severe non missile traumatic brain injury (nmTBI) without macroscopic focal lesions and we found brain atrophy involving the hippocampus, fornix, corpus callosum, optic chiasm, and optic radiations. Memory test scores correlated mainly with fornix volumes [37,38]. In the present study, we re-examined 11 of these nmTBI subjects approximately 8 yr later. High-spatial resolution T1 weighted magnetic resonance images of the brain (1mm(3)) and standardised memory tests were performed once more in order to compare brain morphology and memory performance originally assessed 3-13 months after head injury (first study) and after 8-10 yr (present study). An overall improvement of memory test performance was demonstrated in the latest assessment, indicating that cognitive recovery in severe nmTBI subjects had not been completed within 3-13 months post-injury. It is notable that the volumes of the fornix and the hippocampus were reduced significantly from normal controls, but these volumes do not differ appreciatively between nmTBI subjects at first (after ∼1 yr) and at second (after ∼8 yr) scans. On the contrary, a clear reduction in the volume of the corpus callosus can be observed after ∼1 yr and a further significant reduction is evident after ∼8 yr, indicating that the neural degeneration in severe nmTBI continues long after the head trauma and relates to specific structures and not to the overall brain.

What does the corpus callosum tell us about brain changes in the elderly?

The corpus callosum is the largest hemispheric interconnection bundle in the human brain. Its anterior-posterior fiber caliber gradient can help in understanding the pathophysiological mechanisms underlying white matter changes both in old age and dementia. Here, the Leukoaraiosis and Disability (LADIS) study, a longitudinal cohort study, which shows an association between corpus callosum atrophy and cognitive and motor decline in the elderly, provides the possibility to consider the use of multimodal macro-microstructural imaging of corpus callosum as a marker of structural brain changes of physiological and pathological aging.

Relationship between brain abnormalities and cognitive profile in Williams syndrome.

Previous studies have shown inconsistent results when reporting brain abnormalities in Williams syndrome (WS). This makes an interpretation of clinical and behavioural data uncertain in terms of anatomical localization of brain tissue changes. In this study we employed voxel based morphometry to directly investigate the regional distribution of grey matter (GM) density as a function of individual neuropsychological profiles in individuals with WS. GM maps were regressed against the neuropsychological measures on which WS individuals performed worse than controls. Results showed an association between the regional GM density in the cerebellum, bilaterally, the right Supplementary Motor Area, the right fusiform gyrus, and measures of morpho-syntactic ability. An association was also found between measures of visuo-spatial and visuo-motor abilities and regional GM density in the left cerebellum, left parietal lobule, right superior and left orbital frontal gyri. The study shows the potential to clarify the anatomical substrate underlying specific cognitive deficits in WS.