Frontostriatal Circuits Alterations Associated with Cognitive Flexibility Deterioration in Huntington's Disease.

BACKGROUND: Recent resting-state functional magnetic resonance imaging studies have reported abnormal functional connectivity (FC) in the prefrontal cortex (PFC)-striatum circuit in patients with premanifest Huntington's disease (HD). However, there is a lack of evidence showing persistence of abnormal frontostriatal FC and its relation to cognitive flexibility performance in patients with clinically manifest HD. OBJECTIVE: The aim of this study was to evaluate the resting-state FC integrity of the frontostriatal circuit and its relation to cognitive flexibility in HD patients and healthy controls (HCs). METHOD: Eighteen patients with early clinical HD manifestation and 18 HCs matched for age, sex, and education participated in this study. Both groups performed the Cambridge Neuropsychological Test Automated Battery (CANTAB) Intra-Extra Dimensional (IED) set-shift task, which measures cognitive flexibility. Resting-state functional magnetic resonance images were also acquired to examine the FC in specific frontostriatal circuits. Eight regions of interest were preselected based on regions previously associated with extradimensional (ED) shifting in patients with premanifest HD. RESULTS: Significant negative correlations between the number of attentional set-shifting errors and the ventral striatum-ventrolateral PFC FC were found in the HD group. This group also showed negative FC correlations between the total errors and the FC between right ventral striatum-right ventrolateral PFC, left ventral striatum-left ventrolateral PFC, and right ventral striatum-left ventrolateral PFC. Negative correlations between the ED errors and left ventral striatum-left ventrolateral PFC and right ventral striatum-right ventrolateral PFC FC were also found. Finally, a positive correlation between the number of stages completed and left ventral striatum-left ventrolateral PFC FC was found. CONCLUSIONS: Manifest HD patients show significant cognitive flexibility deficits in attentional set-shifting that are associated with FC alterations in the frontostriatal circuit. These results show that FC abnormalities found in the prodromal stage of the disease can also be associated with cognitive flexibility deficits at a later clinical stage, making them good candidates to be explored in longitudinal studies.

Cognitive Impairments in Spinocerebellar Ataxia Type 10 and Their Relation to Cortical Thickness.

BACKGROUND: Spinocerebellar ataxia type 10 is a neurodegenerative disorder caused by the expansion of an ATTCT pentanucleotide repeat. Its clinical features include ataxia and, in some cases, epileptic seizures. There is, however, a dearth of information about its cognitive deficits and the neural bases underpinning them. OBJECTIVES: The objectives of this study were to characterize the performance of spinocerebellar ataxia type 10 patients in 2 cognitive domains typically affected in spinocerebellar ataxias, memory and executive function, and to correlate the identified cognitive impairments with ataxia severity and cerebral/cerebellar cortical thickness, as quantified by MRI. METHODS: Memory and executive function tests were administered to 17 genetically confirmed Mexican spinocerebellar ataxia type 10 patients, and their results were compared with 17 healthy matched volunteers. MRI was performed in 16 patients. RESULTS: Patients showed deficits in visual and visuospatial short-term memory, reduced storage capacity for verbal memory, and impaired monitoring, planning, and cognitive flexibility, which were ataxia independent. Patients with seizures (n = 9) and without seizures (n = 8) did not differ significantly in cognitive performance. There were significant correlations between short-term visuospatial memory impairment and posterior cerebellar lobe cortical thickness (bilateral lobule VI, IX, and right X). Cognitive flexibility deficiencies correlated with cerebral cortical thickness in the left middle frontal, cingulate, opercular, and temporal gyri. Cerebellar cortical thickness in several bilateral regions was correlated with motor impairment. CONCLUSIONS: Patients with spinocerebellar ataxia type 10 show significant memory and executive dysfunction that can be correlated with deterioration in the posterior lobe of the cerebellum and prefrontal, cingulate, and middle temporal cortices. © 2021 International Parkinson and Movement Disorder Society.

Cerebellar Degeneration Signature in Huntington's Disease.

Recent findings suggest a significant effect of the cerebellar circuit deterioration on the clinical manifestation of Huntington's disease, calling for a better understanding of the cerebellar degeneration in this disorder. Recent brain imaging analyses have provided conflicting results regarding the cerebellar changes during the progression of this disease. To help in resolving this controversy, we examined the cerebellar gray matter structural integrity from a cohort of HD patients. Whole brain voxel-based morphometry (VBM) and spatially unbiased atlas template of the human cerebellum (SUIT) analyses were done from T1-weighted brain images. Our results showed a significant cerebellar degeneration without any sign of volume increase. The highest cerebellar degeneration was identified in Crus I right lobule, Crus II bilaterally, and left VIIb, and left VIIIa lobules. The cerebellar degeneration signature, which controls for severity of degeneration, showed a degeneration pattern that included regions I-IV, Crus II, VIIb, VIIIa, VIIIb and X.

Procedural and Strategic Visuomotor Learning Deficits in Children With Developmental Coordination Disorder.

Purpose: Developmental coordination disorder (DCD) is characterized by poor coordination and clumsiness in children. Subjects often show unsteady gait, frequent tripping, and difficulty holding objects. Here we evaluated the implicit and explicit motor learning capabilities of children with DCD. Method: We assessed a total of 80 children (4-12 years old). These children were divided into two groups of 40 participants each. One group with DCD diagnosis and a control group. Using a prism adaptation paradigm, we evaluated whether DCD affects procedural visuomotor adaptation. This adaptation typically occurs during the laterally displacing prism adaptation task. We contrasted these results with the performance during a reversing prism adaptation task, which mainly places demands on strategic visuomotor learning. To solve both adaptation tasks, subjects must perform the same movements, but using two completely different approaches. Results: There was a significant variable error difference between groups, confirming a motor control deficit in individuals with DCD. This group also showed significant visuomotor learning deficits in the displacing task, including less adaptation and smaller aftereffect. The analysis on the reversing task revealed a significant larger number of subjects with DCD that could not adapt, suggesting significant strategic visuomotor learning deficits in this group too. Conclusions: These results demonstrate procedural and strategic visuomotor deficits in this sample of children with DCD.

Implicit learning impairment identified via predictive saccades in Huntington's disease correlates with extended cortico-striatal atrophy.

The ability to anticipate events and execute motor commands prior to a sensory event is an essential capability for human's everyday life. This implicitly learned anticipatory behavior depends on the past performance of repeated sensorimotor interactions timed with external cues. This kind of predictive behavior has been shown to be compromised in neurological disorders such as Huntington disease (HD), in which neural atrophy includes key cortical and basal ganglia regions. To investigate the neural basis of the anticipatory behavioral deficits in HD we used a predictive-saccade paradigm that requires predictive control to generate saccades in a metronomic temporal pattern. This is ideal because the integrity of the oculomotor network that includes the striatum and prefrontal, parietal, occipital and temporal cortices can be analyzed using structural MRI. Our results showed that the HD patients had severe predictive saccade deficits (i.e., an inability to reduce saccade reaction time in predictive condition), which are accentuated in patients with more severe motor deterioration. Structural imaging analyses revealed that these anticipatory deficits correlated with grey-matter atrophy in frontal, parietal-occipital and striatal regions. These findings indicate that the predictive saccade control deficits in HD are related to an extended cortico-striatal atrophy. This suggests that eye movement measurement could be a reliable marker of the progression of cognitive deficits in HD.

Extensive cerebellar and thalamic degeneration in spinocerebellar ataxia type 10.

INTRODUCTION: Spinocerebellar ataxia type 10 (SCA10) is a hereditary neurodegenerative disorder caused by repeat expansions in the ATXN10 gene. Patients present with cerebellar ataxia frequently accompanied by seizures. Even though loss of cerebellar Purkinje neurons has been described, its brain degeneration pattern is unknown. Our aim was to characterize the gray and white matter degeneration patterns in SCA10 patients and the association with clinical features. METHODS: We enrolled 18 patients with molecular diagnosis of SCA10 and 18 healthy individuals matched for age and sex. All participants underwent brain MRI including high-resolution anatomical and diffusion images. Whole-brain Tract-Based Spatial Statistics (TBSS) and Voxel-Based Morphometry (VBM) were performed to identify white and grey matter degeneration respectively. A second analysis in the cerebellum identified the unbiased pattern of degeneration. Motor impairment was assessed using the SARA Scale. RESULTS: TBSS analysis in the patient group revealed white matter atrophy exclusively in the cerebellum. VBM analysis showed extensive grey matter degeneration in the cerebellum, brainstem, thalamus, and putamen. Significant associations between cerebellar degeneration and SARA scores were found. Additionally, degeneration in thalamic GM and WM in the cerebellar lobule VI were significantly associated with the presence of seizures. CONCLUSION: The results show that besides cerebellum and brainstem, brain degeneration in SCA10 includes predominantly the putamen and thalamus; involvement of the latter is strongly associated with seizures. Analysis of the unbiased degeneration pattern in the cerebellum suggests lobules VIIIb, IX, and X as the primary cerebellar targets of the disease, which expands to the anterior lobe in later stages.

Neuroanatomical substrates involved in unrelated false facial recognition.

Identifying faces is a process central for social interaction and a relevant factor in eyewitness theory. False recognition is a critical mistake during an eyewitness's identification scenario because it can lead to a wrongful conviction. Previous studies have described neural areas related to false facial recognition using the standard Deese/Roediger-McDermott (DRM) paradigm, triggering related false recognition. Nonetheless, misidentification of faces without trying to elicit false memories (unrelated false recognition) in a police lineup could involve different cognitive processes, and distinct neural areas. To delve into the neural circuitry of unrelated false recognition, we evaluated the memory and response confidence of participants while watching faces photographs in an fMRI task. Functional activations of unrelated false recognition were identified by contrasting the activation on this condition vs. the activations related to recognition (hits) and correct rejections. The results identified the right precentral and cingulate gyri as areas with distinctive activations during false recognition events suggesting a conflict resulting in a dysfunction during memory retrieval. High confidence suggested that about 50% of misidentifications may be related to an unconscious process. These findings add to our understanding of the construction of facial memories and its biological basis, and the fallibility of the eyewitness testimony.

Voluntary saccade inhibition deficits correlate with extended white-matter cortico-basal atrophy in Huntington's disease.

The ability to inhibit automatic versus voluntary saccade commands in demanding situations can be impaired in neurodegenerative diseases such as Huntington's disease (HD). These deficits could result from disruptions in the interaction between basal ganglia and the saccade control system. To investigate voluntary oculomotor control deficits related to the cortico-basal circuitry, we evaluated early HD patients using an interleaved pro- and anti-saccade task that requires flexible executive control to generate either an automatic response (look at a peripheral visual stimulus) or a voluntary response (look away from the stimulus in the opposite direction). The impairments of HD patients in this task are mainly attributed to degeneration in the striatal medium spiny neurons leading to an over-activation of the indirect-pathway thorough the basal ganglia. However, some studies have proposed that damage outside the indirect-pathway also contribute to executive and saccade deficits. We used the interleaved pro- and anti-saccade task to study voluntary saccade inhibition deficits, Voxel-based morphometry and Tract-based spatial statistic to map cortico-basal ganglia circuitry atrophy in HD. HD patients had voluntary saccade inhibition control deficits, including increased regular-latency anti-saccade errors and increased anticipatory saccades. These deficits correlated with white-matter atrophy in the inferior fronto-occipital fasciculus, anterior thalamic radiation, anterior corona radiata and superior longitudinal fasciculus. These findings suggest that cortico-basal ganglia white-matter atrophy in HD, disrupts the normal connectivity in a network controlling voluntary saccade inhibitory behavior beyond the indirect-pathway. This suggests that in vivo measures of white-matter atrophy can be a reliable marker of the progression of cognitive deficits in HD.

Cognitive Deficits Correlate with White Matter Deterioration in Spinocerebellar Ataxia Type 2.

OBJECTIVES: The aim of this study was to explore the relationship between cognitive and white matter deterioration in a group of participants with spinocerebellar ataxia type 2 (SCA2). METHODS: Fourteen genetically confirmed participants with SCA2 and 14 aged-matched controls participated in the study. Diffusion tensor imaging tract-based spatial statistics were performed to analyze structural white matter integrity. Significant group differences in the mean diffusivity were correlated with SCA2 cognitive deficits. RESULTS: Our analysis revealed higher mean diffusivity in the SCA2 group in cerebellar white matter, medial lemniscus, and middle cerebellar peduncle, among other regions. Cognitive scores correlated with white matter mean diffusivity in the parahippocampal area, inferior frontal and supramarginal gyri and the stria terminalis. CONCLUSIONS: Our findings show significant correlations between white matter microstructural damage in key areas affected in SCA2 and cognitive deficits. These findings result in a more comprehensive understanding of the effect of the neurodegenerative process in people with SCA2.

The Effect of Spatial Working Memory Deterioration on Strategic Visuomotor Learning across Aging.

OBJECTIVE: To evaluate the effect of age-related cognitive changes in a visuomotor learning task that depends on strategic control and contrast it with the effect in a task principally depending on visuomotor recalibration. METHODS: Participants performed a ball throwing task while donning either a reversing dove prism or a displacement wedge prism, which mainly depend on strategic control or visuomotor recalibration, respectively. Visuomotor performance was then analysed in relation to rule acquisition and reversal, recognition memory, visual memory, spatial planning, and spatial working memory with tasks from the Cambridge Neuropsychological Test Automated Battery (CANTAB). RESULTS: The results confirmed previous works showing a detrimental effect of age on visuomotor learning. The analyses of the cognitive changes observed across age showed that both strategic control and visuomotor recalibration had significant negative correlations only with the number of errors in the spatial working memory task. However, when the effect of aging was controlled, the only significant correlation remaining was between the reversal adaptation magnitude and spatial working memory. DISCUSSION: These results suggest that spatial working memory decline across aging could contribute to age-dependent deterioration in both visuomotor learning processes. However, spatial working memory integrity seems to affect strategic learning decline even after controlling for aging.

Effects of aging on strategic-based visuomotor learning.

There are different kinds of visuomotor learnings. One of the most studied is error-based learning where the information about the sign and magnitude of the error is used to update the motor commands. However, there are other instances where subjects show visuomotor learning even if the use of error sign and magnitude information is precluded. In those instances subjects could be using strategic instead of procedural adaptation mechanisms. Here, we present the results of the effect of aging on visuomotor strategic learning under a reversed error feedback condition, and its contrast with procedural visuomotor learning within the same participants. A number of measures were obtained from a task consisting of throwing clay balls to a target before, during and after wearing lateral displacing or reversing prisms. The displacing prism results show an age dependent decrease on the learning rate that corroborates previous findings. The reversing prism results also show significant adaptation impairment in the aged population. However, decreased reversing learning in the older group was the result of an increase in the number of subjects that could not adapt to the reversing prism, and not on a reduction of the learning capacity of all the individuals of the group. These results suggest a significant deleterious effect of aging on visuomotor strategic learning implementation.

Strategy use, planning, and rule acquisition deficits in spinocerebellar ataxia type 2 patients.

Our goal was to improve spinocerebellar ataxia type 2 (SCA2) cognitive profile characterization by testing the hypothesis that strategy, planning and rule acquisition capacities are affected in SCA2. Forty one patients with SCA2 were evaluated with the Spatial Working Memory (SWM), the Stockings of Cambridge (SOC), and the Intra-Extra Dimensional Shift (IED) tests of the Executive module of the Cambridge Neuropsychological Testing Automated Battery (CANTAB). Paired Associates Learning (PAL) and Delayed Matching to Sample (DMS) from the CANTAB memory module were also assessed to corroborate previous findings. Motor deterioration was measured using the Scale for the Assessment and Rating of Ataxia (SARA). We found significant SCA2 related deficits in strategy, planning, and rule acquisition. Our results also corroborated significant memory deficits in these patients with SCA2. Further analysis also showed that patients with large motor deterioration had poorer associative learning and spatial planning scores. Patients with SCA2 show strategy, planning, and rule acquisition deficits as revealed with the CANTAB battery. These deficits should be noted when planning an effective therapy for these patients.

Comprehensive study of early features in spinocerebellar ataxia 2: delineating the prodromal stage of the disease.

The prodromal phase of spinocerebellar ataxias (SCAs) has not been systematically studied. Main findings come from a homogeneous SCA type 2 (SCA2) population living in Cuba. The aim of this study was to characterize extensively the prodromal phase of SCA2 by several approaches. Thirty-seven non-ataxic SCA2 mutation carriers and its age- and sex-matched controls underwent clinical assessments, including standardized neurological exam, structured interviews and clinical scales, and looking for somatic and autonomic features, as well as a neuropsychological battery, antisaccadic recordings, and MRI scans. Main clinical somatic features of non-ataxic mutation carriers were cramps, sensory symptoms, sleep disorders, and hyperreflexia, whereas predominating autonomic symptoms were pollakiuria/nocturia, constipation, and frequent throat clearing. Cognitive impairments included early deficits of executive functions and visual memory, suggesting the involvement of cerebro-cerebellar-cerebral loops and/or reduced cholinergic basal forebrain input to the cortex. Antisaccadic task revealed impaired oculomotor inhibitory control but preserved ability for error correction. Cognitive and antisaccadic deficits were higher as carriers were closer to the estimated onset of ataxia, whereas higher Scale for the Assessment and Rating of Ataxia (SARA) scores were associated most notably to vermis atrophy. The recognition of early features of SCA2 offers novel insights into the prodromal phase and physiopathological base of the disease, allowing the assessment of its progression and the efficacy of treatments, in particular at early phases when therapeutical options should be most effective.

Spinocerebellar ataxia type 2 neurodegeneration differentially affects error-based and strategic-based visuomotor learning.

There are different types of visuomotor learning. Among the most studied is motor error-based learning where the sign and magnitude of the error are used to update motor commands. However, there are other instances where individuals show visuomotor learning even if the sign or magnitude of the error is precluded. Studies with patients suggest that the former learning is impaired after cerebellar lesions, while basal ganglia lesions disrupt the latter. Nevertheless, the cerebellar role is not restricted only to error-based learning, but it also contributes to several cognitive processes. Therefore, here, we tested if cerebellar ataxia patients are affected in two tasks, one that depends on error-based learning and the other that prevents the use of error-based learning. Our results showed that cerebellar patients have deficits in both visuomotor tasks; however, while error-based learning tasks deficits correlated with the motor impairments, the motor error-dependent task did not correlate with any motor measure.