Neuroimaging and serum biomarkers of neurodegeneration and neuroplasticity in Parkinson's disease patients treated by intermittent theta-burst stimulation over the bilateral primary motor area: a randomized, double-blind, sham-controlled, crossover trial study.

Background and objectives: Intermittent theta-burst stimulation (iTBS) is a patterned form of excitatory transcranial magnetic stimulation that has yielded encouraging results as an adjunctive therapeutic option to alleviate the emergence of clinical deficits in Parkinson's disease (PD) patients. Although it has been demonstrated that iTBS influences dopamine-dependent corticostriatal plasticity, little research has examined the neurobiological mechanisms underlying iTBS-induced clinical enhancement. Here, our primary goal is to verify whether iTBS bilaterally delivered over the primary motor cortex (M1) is effective as an add-on treatment at reducing scores for both motor functional impairment and nonmotor symptoms in PD. We hypothesize that these clinical improvements following bilateral M1-iTBS could be driven by endogenous dopamine release, which may rebalance cortical excitability and restore compensatory striatal volume changes, resulting in increased striato-cortico-cerebellar functional connectivity and positively impacting neuroglia and neuroplasticity. Methods: A total of 24 PD patients will be assessed in a randomized, double-blind, sham-controlled crossover study involving the application of iTBS over the bilateral M1 (M1 iTBS). Patients on medication will be randomly assigned to receive real iTBS or control (sham) stimulation and will undergo 5 consecutive sessions (5 days) of iTBS over the bilateral M1 separated by a 3-month washout period. Motor evaluation will be performed at different follow-up visits along with a comprehensive neurocognitive assessment; evaluation of M1 excitability; combined structural magnetic resonance imaging (MRI), resting-state electroencephalography and functional MRI; and serum biomarker quantification of neuroaxonal damage, astrocytic reactivity, and neural plasticity prior to and after iTBS. Discussion: The findings of this study will help to clarify the efficiency of M1 iTBS for the treatment of PD and further provide specific neurobiological insights into improvements in motor and nonmotor symptoms in these patients. This novel project aims to yield more detailed structural and functional brain evaluations than previous studies while using a noninvasive approach, with the potential to identify prognostic neuroprotective biomarkers and elucidate the structural and functional mechanisms of M1 iTBS-induced plasticity in the cortico-basal ganglia circuitry. Our approach may significantly optimize neuromodulation paradigms to ensure state-of-the-art and scalable rehabilitative treatment to alleviate motor and nonmotor symptoms of PD.

Neuropsychiatric Symptoms in Clinically Defined Parkinson's Disease: An Updated Review of Literature.

Background: Neuropsychiatric symptoms (NPS) are a common and potentially serious manifestation of Parkinson's disease (PD) but are frequently overlooked in favor of a focus on motor symptomatology. Here, we conducted a literature review of the prevalence and type of NPS experienced by PD patients with a clinically defined course of their illness. Methods: We identified reports of NPS in patients with PD and mean disease duration over 3 years. Three databases-PubMed, Scopus, and Dialnet-were searched for relevant literature published between 2010 and 2020. Predefined exclusion criteria were applied prior to a descriptive analysis of the literature base. Results: In all, 87 unique reports were identified and 30 met inclusion and exclusion criteria. These included 7142 patients with PD (male: 67.3%; mean age: 66.2 years; mean disease duration: 6.7 years). The most frequent NPS were mood disorders (apathy, depression, and anxiety), psychosis, and impulse control disorders (ICD). Treatment with dopamine agonists was identified as an important risk factor for ICD. Co-occurrence of NPS and cognitive dysfunction was also evidenced in a number of studies. Patients with more significant cognitive deficits and higher levels of NPS appeared to be of older age with a longer disease duration and to have more severe motor symptoms. Conclusions: NPS, most commonly mood disorders (apathy, depression, and anxiety), psychosis, and ICDs are frequent manifestations of PD. The results of this review reflect the need to develop unified validated assessment protocols for NPS in PD, as well as to improve their management in clinical practice.

Subthalamic Beta Activity in Parkinson's Disease May Be Linked to Dorsal Striatum Gray Matter Volume and Prefrontal Cortical Thickness: A Pilot Study.

Background: Excessive oscillations at beta frequencies (13-35 Hz) in the subthalamic nucleus (STN) represent a pathophysiological hallmark of Parkinson's disease (PD), which correlates well with parkinsonian symptoms and is reduced in response to standard disease treatments. However, the association of disease-specific regional gray matter (GM) atrophy or cortical thickness (CT) with the presence of STN beta oscillatory activity has been poorly investigated but is of relevance given the potential of these variables for extracting information about PD pathophysiology. This exploratory study investigated the involvement of regional GM volume and CT in the basal ganglia-cortical network and its potential association with the presence of STN beta oscillatory activity in PD. Methods: We acquired preoperative GM densities on T1-weighted magnetic resonance imaging scans and we carried out regional estimation of GM volume and CT. LFP activities from the STN were recorded post-operatively in 7 cognitively preserved PD patients off dopaminergic medication undergoing deep-brain stimulation surgery. Oscillatory beta power was determined by power spectral density of 4-min resting state STN LFP activity. Spearman partial correlations and regression analysis were used to screen the presence of STN beta power for their relationship with GM volume and CT measurements. Results: After controlling for the effects of age, educational level, and disease duration, and after correcting for multiple testing, enhanced STN beta power showed significant and negative correlations between, first, volume of the right putamen and left caudate nucleus, and second, smaller CT in frontal regions involving the left rostral middle frontal gyrus (MFG) and left medial orbitofrontal gyrus. A lower volume in the right putamen and a lower CT in the left MFG demonstrated the strongest associations with increased STN beta power. Conclusions: These tentative results seem to suggest that STN LFP beta frequencies may be mainly linked to different but ongoing parallel neurodegenerative processes, on the one hand, to GM volume reduction in dorsal striatum, and on the other hand, to CT reduction of prefrontal-"associative" regions. These findings could further delineate the brain structural interactions underpinning the exaggerated STN beta activity commonly observed in PD patients.

Cortical Thickness and Serum NfL Explain Cognitive Dysfunction in Newly Diagnosed Patients With Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: To determine the relative importance of global or regional MRI and blood markers of neurodegeneration and neuroaxonal injury in predicting cognitive performance for recently diagnosed patients with multiple sclerosis (MS). METHODS: Thirty-five newly diagnosed patients with relapsing-remitting MS (RRMS) and 23 healthy controls (HCs) simultaneously completed a full clinical and neuropsychological assessment, structural brain MRI, and serum neurofilament light chain (sNfL) level test. Linear regression analyses were performed to determine which global or regional measures of gray matter (GM) atrophy and cortical thickness (CT), in combination with sNfL levels and clinical scores, are most strongly related to neuropsychological impairment. RESULTS: Compared with HCs, patients with MS showed bilateral thalamic GM atrophy (left, p = 0.033; right, p = 0.047) and diminished CT, particularly in the right superior and transverse temporal gyri (p = 0.045; p = 0.037). Regional atrophy failed to add predictive variance, whereas anxiety symptoms, sNfL, and global CT were the best predictors (R2 = 0.404; p < 0.001) of cognitive outcomes, with temporal thickness accounting for greater variance in cognitive deficits than global CT. DISCUSSION: Thalamic GM atrophy and thinning in temporal regions represent a distinctive MRI trait in the early stages of MS. Although sNfL levels alone do not clearly differentiate HCs and patients with RRMS, in combination with global and regional CT, sNfL levels can better explain the presence of underlying cognitive deficits. Hence, cortical thinning and sNfL increases can be considered 2 parallel neurodegenerative markers in the pathogenesis of progression in newly diagnosed patients with MS.

Nucleus Accumbens Stimulation Modulates Inhibitory Control by Right Prefrontal Cortex Activation in Obsessive-Compulsive Disorder.

Inhibitory control is considered a compromised cognitive function in obsessive-compulsive (OCD) patients and likely linked to corticostriatal circuitry disturbances. Here, 9 refractory OCD patients treated with deep brain stimulation (DBS) were evaluated to address the dynamic modulations of large-scale cortical network activity involved in inhibitory control after nucleus accumbens (NAc) stimulation and their relationship with cortical thickness. A comparison of DBS "On/Off" states showed that patients committed fewer errors and exhibited increased intraindividual reaction time variability, resulting in improved goal maintenance abilities and proactive inhibitory control. Visual P3 event-related potentials showed increased amplitudes during Go/NoGo performance. Go and NoGo responses increased cortical activation mainly over the right inferior frontal gyrus and medial frontal gyrus, respectively. Moreover, increased cortical activation in these areas was equally associated with a higher cortical thickness within the prefrontal cortex. These results highlight the critical role of NAc DBS for preferentially modulating the neuronal activity underlying sustained speed responses and inhibitory control in OCD patients and show that it is triggered by reorganizing brain functions to the right prefrontal regions, which may depend on the underlying cortical thinning. Our findings provide updated structural and functional evidence that supports critical dopaminergic-mediated frontal-striatal network interactions in OCD.

Do Gender-Related Stereotypes Affect Spatial Performance? Exploring When, How and to Whom Using a Chronometric Two-Choice Mental Rotation Task.

It is a common belief that males have superior visuospatial abilities and that differences in this and other cognitive domains (e.g., math) contribute to the reduced interest and low representation of girls and women in STEM education and professions. However, previous studies show that gender-related implicit associations and explicit beliefs, as well as situational variables, might affect cognitive performance in those gender-stereotyped domains and produce between-gender spurious differences. Therefore, the present study aimed to provide information on when, how and who might be affected by the situational reactivation of stereotypic gender-science beliefs/associations while performing a 3D mental rotation chronometric task (3DMRT). More specifically, we assessed the explicit beliefs and implicit associations (by the Implicit Association Test) held by female and male students of humanities and STEM majors and compared their performance in a 3DMRT after receiving stereotype- congruent, incongruent and nullifying experimental instructions. Our results show that implicit stereotypic gender-science associations correlate with 3DMRT performance in both females and males, but that inter-gender differences emerge only under stereotype-reactivating conditions. We also found that changes in self-confidence mediate these instructions' effects and that academic specialization moderates them, hence promoting 3DMRT performance differences between male and female humanities, but not STEM, students. Taken together, these observations suggest that the common statement "males have superior mental rotation abilities" simplifies a much more complex reality and might promote stereotypes which, in turn, might induce artefactual performance differences between females and males in such tasks.

Subcortical grey matter structures in multiple sclerosis: what is their role in cognition?

The present study aimed to investigate altered grey matter (GM) and functional connectivity (FC) in deep subcortical areas, such as the thalamus and basal ganglia, and their relationship with cognitive impairment (CI) in multiple sclerosis (MS). Thirty-six patients were neuropsychologically assessed, classified as cognitive preserved (CP) and CI, and were compared with 18 healthy controls. GM atrophy and FC were observed in 10 predefined functional areas of the thalamus and in six of basal ganglia. GM atrophy was prominent in the basal ganglia in CI patients compared with CP MS patients. Increased FC was observed between the right caudate and the bilateral orbitofrontal cortex in CI versus CP patients. The discriminant and correlation analyses showed that the enhanced FC observed between the right caudate and the orbitofrontal cortex was closely associated with CI in MS patients. In conclusion, reduced GM volume and enhanced frontobasal ganglia connectivity are related to cognition in MS patients.

Cambios estructurales y funcionales del hipocampo en pacientes con esclerosis múltiple y su relación con procesos de memoria / Structural and functional changes of the hippocampus in patients with multiple sclerosis and their relationship with memory processes

Introducción. Una de las alteraciones cognitivas más prevalentes en los pacientes con esclerosis múltiple son los problemas de codificación de la información (tanto verbal como visual), proceso relacionado con el hipocampo. Objetivo. Estudiar la relación entre los procesos de aprendizaje y retención de la información a largo plazo con el volumen hipocampal y la conectividad funcional (CF) en pacientes con esclerosis múltiple comparados con un grupo control. Sujetos y métodos. Ambos grupos fueron evaluados con la batería neuropsicológica breve, que incluye pruebas de memoria verbal y visual. Se realizó el estudio de volumetría de la sustancia gris mediante la técnica de morfometría basada en el vóxel y un estudio de CF de vóxel de semilla centrado en la zona de interés (hipocampo). Se realizaron análisis de asociación entre rendimiento en memoria y cambios volumétricos y de CF. Resultados. Los resultados mostraron atrofia en la sustancia gris en el hipocampo izquierdo y una menor CF entre el hipocampo izquierdo y el troncoencéfalo, el cerebelo, el giro fusiforme y el giro temporal superior en los pacientes respecto al grupo control. En el grupo de pacientes se observa una correlación positiva entre la sustancia gris en ambos hipocampos y el rendimiento en memoria verbal, así como una correlación positiva entre el rendimiento en memoria visual y la CF entre el hipocampo izquierdo y diversas regiones temporales. Conclusiones. Los resultados muestran una relación entre el rendimiento de memoria verbal y visual, y cambios estructurales y funcionales en el hipocampo en pacientes con esclerosis múltiple (AU)

Introduction. One of the most prevalent cognitive deficits in multiple sclerosis (MS) patients relates to (both verbal and visual) information encoding, a process related the hippocampus. Aim. To assess the relationship between information learning and long-term retention processes and hippocampal volume and functional connectivity (FC) in MS patients. Subjects and methods. MS patients and a control group of healthy volunteers were assessed using the brief neuropsychological battery, which includes tests of verbal and visual memory. Gray matter volume was assessed through the voxel based morphometry technique, and a study of seed-based FC focused on the region of interest (hippocampus) was also conducted. Results. Results revealed that, as compared to the control group, MS patients display gray matter atrophy at the left hippocampus gray matter and smaller FC between left hippocampus and brainstem, cerebellum, fusiform gyrus and superior temporal gyrus. Association analyses were performed between memory tests performance and both volumetric and FC changes. Results showed a positive correlation between gray matter hippocampal (bilateral) volume and verbal memory performance of the MS group. Further, in MS patients, a positive correlation between visual memory performance and FC between the left hippocampus and several temporal regions was also found. Conclusions. The results of the present study reveal a relationship between structural and functional changes in the hippocampus of MS patients and their performance on verbal and visual memory tests (AU)

[Structural and functional changes of the hippocampus in patients with multiple sclerosis and their relationship with memory processes]. / Cambios estructurales y funcionales del hipocampo en pacientes con esclerosis múltiple y su relación con procesos de memoria.

INTRODUCTION: One of the most prevalent cognitive deficits in multiple sclerosis (MS) patients relates to (both verbal and visual) information encoding, a process related the hippocampus. AIM: To assess the relationship between information learning and long-term retention processes and hippocampal volume and functional connectivity (FC) in MS patients. SUBJECTS AND METHODS: MS patients and a control group of healthy volunteers were assessed using the brief neuro-psychological battery, which includes tests of verbal and visual memory. Gray matter volume was assessed through the voxel based morphometry technique, and a study of seed-based FC focused on the region of ??interest (hippocampus) was also conducted. RESULTS: Results revealed that, as compared to the control group, MS patients display gray matter atrophy at the left hippocampus gray matter and smaller FC between left hippocampus and brainstem, cerebellum, fusiform gyrus and superior temporal gyrus. Association analyses were performed between memory tests performance and both volumetric and FC changes. Results showed a positive correlation between gray matter hippocampal (bilateral) volume and verbal memory performance of the MS group. Further, in MS patients, a positive correlation between visual memory performance and FC between the left hippocampus and several temporal regions was also found. CONCLUSIONS: The results of the present study reveal a relationship between structural and functional changes in the hippocampus of MS patients and their performance on verbal and visual memory tests.

TITLE: Cambios estructurales y funcionales del hipocampo en pacientes con esclerosis multiple y su relacion con procesos de memoria.Introduccion. Una de las alteraciones cognitivas mas prevalentes en los pacientes con esclerosis multiple son los problemas de codificacion de la informacion (tanto verbal como visual), proceso relacionado con el hipocampo. Objetivo. Estudiar la relacion entre los procesos de aprendizaje y retencion de la informacion a largo plazo con el volumen hipocampal y la conectividad funcional (CF) en pacientes con esclerosis multiple comparados con un grupo control. Sujetos y metodos. Ambos grupos fueron evaluados con la bateria neuropsicologica breve, que incluye pruebas de memoria verbal y visual. Se realizo el estudio de volumetria de la sustancia gris mediante la tecnica de morfometria basada en el voxel y un estudio de CF de voxel de semilla centrado en la zona de interes (hipocampo). Se realizaron analisis de asociacion entre rendimiento en memoria y cambios volumetricos y de CF. Resultados. Los resultados mostraron atrofia en la sustancia gris en el hipocampo izquierdo y una menor CF entre el hipocampo izquierdo y el troncoencefalo, el cerebelo, el giro fusiforme y el giro temporal superior en los pacientes respecto al grupo control. En el grupo de pacientes se observa una correlacion positiva entre la sustancia gris en ambos hipocampos y el rendimiento en memoria verbal, asi como una correlacion positiva entre el rendimiento en memoria visual y la CF entre el hipocampo izquierdo y diversas regiones temporales. Conclusiones. Los resultados muestran una relacion entre el rendimiento de memoria verbal y visual, y cambios estructurales y funcionales en el hipocampo en pacientes con esclerosis multiple.

The link between resting-state functional connectivity and cognition in MS patients.

OBJECTIVE: The objective of this paper is to explore differences in resting-state functional connectivity between cognitively impaired and preserved multiple sclerosis (MS) patients. METHODS: Sixty MS patients and 18 controls were assessed with the Brief Repeatable Battery of Neuropsychological Tests (BRB-N). A global Z score of the BRB-N was obtained and allowed us to classify MS patients as cognitively impaired and cognitively preserved (n = 30 per group). Functional connectivity was assessed by independent component analysis of resting-state networks (RSNs) related to cognition: the default mode network, left and right frontoparietal and salience network. Between-group differences were evaluated and a regression analysis was performed to describe relationships among cognitive status, functional connectivity and radiological variables. RESULTS: Compared to cognitively preserved patients and healthy controls, cognitively impaired patients showed a lesser degree of functional connectivity in all RSNs explored. Cognitively preserved patients presented less connectivity than the control group in the left frontoparietal network. Global Z scores were positively and negatively correlated with brain parenchymal fraction and lesion volume, respectively. CONCLUSION: Decreased cognitive performance is accompanied by reduced resting state functional connectivity and directly related to brain damage. These results support the use of connectivity as a powerful tool to monitor and predict cognitive impairment in MS patients.