Localization and Network Connectivity of Lesions Causing Limb Ataxia in Patients With Stroke.

BACKGROUND AND OBJECTIVES: Ataxia is primarily considered to originate from the cerebellum. However, it can manifest without obvious cerebellar damage, such as in anterior circulation stroke, leaving the mechanisms of ataxia unclear. The aim of this study was to investigate whether stroke lesions causing limb ataxia localize to a common brain network. METHODS: In this prospective cohort study, adult patients with new-onset stroke with visible lesions on CT or MRI from Turku University Hospital, Finland, were clinically examined (1) after their stroke while still admitted to the hospital (baseline) and (2) 4 months later (follow-up) to assess limb ataxia. Lesion locations and their functional connectivity, computed using openly available data from 1,000 healthy volunteers from the Brain Genome Superstruct Project, were compared voxel-by-voxel across the whole brain between patients with and without ataxia, using voxel-based lesion-symptom mapping and lesion network mapping. The findings were confirmed in an independent stroke patient cohort with identical clinical assessments. RESULTS: One hundred ninety-seven patients (mean age 67.2 years, 39%female) were included in this study. At baseline, 35 patients (68.3 years, 34%female) had and 162 (67.0 years, 40%female) did not have new-onset acute limb ataxia. At follow-up, additional 4 patients had developed late-onset limb ataxia, totalling to 39 patients (68.6 years, 36%female) with limb ataxia at any point. One hundred eighteen patients (66.2 years, 40%female) did not have ataxia at any point (n = 40 with missing follow-up data). Lesions in 54% of the patients with acute limb ataxia were located outside the cerebellum and cerebellar peduncles, and we did not find an association between specific lesion locations and ataxia. Lesions causing acute limb ataxia, however, were connected to a common network centered on the intermediate zone cerebellum and cerebellar peduncles (lesion connectivity in patients with vs without acute limb ataxia, pFWE < 0.05). The results were similar when comparing patients with and without ataxia at any point, and when excluding lesions in the cerebellum and cerebellar peduncles (pFWE < 0.05). The findings were confirmed in the independent stroke dataset (n = 96), demonstrating an OR of 2.27 (95% CI 1.32-3.91) for limb ataxia per standard deviation increase in limb ataxia network damage score. DISCUSSION: Lesions causing limb ataxia occur in heterogeneous locations but localize to a common brain network.

Frontal white and gray matter abnormality in gambling disorder: A multimodal MRI study.

Background: Changes in brain structural connections appear to be important in the pathophysiology of substance use disorders, but their role in behavioral addictions, such as gambling disorder (GD), is unclear. GD also offers a model to study addiction mechanisms without pharmacological confounding factors. Here, we used multimodal MRI data to examine the integrity of white matter connections in individuals with GD. We hypothesized that the affected areas would be in the fronto-striatal-thalamic circuit. Methods: Twenty individuals with GD (mean age: 64 years, GD duration: 15.7 years) and 40 age- and sex-matched healthy controls (HCs) underwent detailed clinical examinations together with brain 3T MRI scans (T1, T2, FLAIR and DWI). White matter (WM) analysis involved fractional anisotropy and lesion load, while gray matter (GM) analysis included voxel- and surface-based morphometry. These measures were compared between groups, and correlations with GD-related behavioral characteristics were examined. Results: Individuals with GD showed reduced WM integrity in the left and right frontal parts of the corona radiata and corpus callosum (pFWE < 0.05). WM gambling symptom severity (SOGS score) was negatively associated to WM integrity in these areas within the left hemisphere (p < 0.05). Individuals with GD also exhibited higher WM lesion load in the left anterior corona radiata (pFWE < 0.05). GM volume in the left thalamus and GM thickness in the left orbitofrontal cortex were reduced in the GD group (pFWE < 0.05). Conclusions: Similar to substance addictions, the fronto-striatal-thalamic circuit is also affected in GD, suggesting that this circuitry may have a crucial role in addictions, independent of pharmacological substances.

Abnormal frontostriatal connectivity and serotonin function in gambling disorder: A preliminary exploratory study.

Background: The neurobiological mechanisms of gambling disorder are not yet fully characterized, limiting the development of treatments. Defects in frontostriatal connections have been shown to play a major role in substance use disorders, but data on behavioral addictions, such as gambling disorder, are scarce. The aim of this study was to 1) investigate whether gambling disorder is associated with abnormal frontostriatal connectivity and 2) characterize the key neurotransmitter systems underlying the connectivity abnormalities. Methods: Fifteen individuals with gambling disorder and 17 matched healthy controls were studied with resting-state functional connectivity MRI and three brain positron emission tomography scans, investigating dopamine (18F-FDOPA), opioid (11C-carfentanil) and serotonin (11C-MADAM) function. Frontostriatal connectivity was investigated using striatal seed-to-voxel connectivity and compared between the groups. Neurotransmitter systems underlying the identified connectivity differences were investigated using region-of-interest and voxelwise approaches. Results: Individuals with gambling disorder showed loss of functional connectivity between the right nucleus accumbens (NAcc) and a region in the right dorsolateral prefrontal cortex (DLPFC) (PFWE <0.05). Similarly, there was a significant Group x right NAcc interaction in right DLPFC 11C-MADAM binding (p = 0.03) but not in 18F-FDOPA uptake or 11C-carfentanil binding. This was confirmed in voxelwise analyses showing a widespread Group x right NAcc interaction in the prefrontal cortex 11C-MADAM binding (PFWE <0.05). Right NAcc 11C-MADAM binding potential correlated with attentional impulsivity in individuals with gambling disorder (r = -0.73, p = 0.005). Discussion: Gambling disorder is associated with right hemisphere abnormal frontostriatal connectivity and serotonergic function. These findings will contribute to understanding the neurobiological mechanism and may help identify potential treatment targets for gambling disorder.