High-Frequency Repetitive Transcranial Magnetic Stimulation Over the Left Dorsolateral Prefrontal Cortex Shortly Alleviates Fatigue in Patients With Multiple System Atrophy: A Randomized Controlled Trial

Background: Fatigue is a common symptom in patients with Multiple system atrophy (MSA), but effective treatments remain elusive. The present study aims to investigate whether high-frequency repetitive transcranial magnetic stimulation (rTMS) over the left dorsolateral prefrontal cortex (DLPFC) could relieve fatigue in patients with MSA.Methods: This is a single-center, randomized and double-blind trial. Twenty-two patients with MSA and fatigue were randomly allocated to receive 10 sessions of either active (N = 11) or sham (N = 11) 10 Hz rTMS over the left DLPFC. The participants were assessed at baseline (T0), after the last session of treatment (T1), and at 2-week (T2), and 4-week (T3) follow-up timepoints. The primary outcomes were Fatigue Severity Scale-9 (FSS-9) scores, with Unified Multiple System Atrophy Rating Scale (UMSARS), 17-item Hamilton Depression Scale (HAMD-17), and Hamilton Anxiety Scale (HAMA) as secondary outcomes.Results: Two-way repeated ANOVAs revealed significant group × time interactions for FSS-9 scores (p < 0.001), HAMD-17 scores (p = 0.01), HAMA scores (p = 0.01), and UMRSA part II (p = 0.05). Post-hoc analyses showed that compared to T0, the active group exhibited remarkable improvements in FSS-9 and UMRSA part II scores at T1 and T2, but not at T3, and also in HAMD-17 and HAMA scores at T1, T2, and T3. No significant improvement was found in the sham group.Conclusion: High-frequency rTMS over the left DLPFC could provide short-term improvements for alleviating fatigue in patients with MSA, but the beneficial effects last no more than 4 weeks.

Progressive Prefrontal Cortex Dysfunction in Parkinson's Disease With Probable REM Sleep Behavior Disorder: A 3-Year Longitudinal Study

This study aimed to explore the disrupted prefrontal cortex activity specific to patients with Parkinson's disease (PD) with rapid eye movement sleep behavior disorder (RBD) compared with those without and to further examine the associations between these alterations and neuropsychological measurements. Ninety-six patients with early PD underwent both structural and functional MRI, and also neuropsychological assessments in the Parkinson's Progression Markers Initiative (PPMI) database. Of these, 46 patients who completed 1- and 3-year fMRI follow-up examinations were categorized as PD with probable RBD (PD-pRBD+) and without (PD-pRBD−). The left dorsolateral prefrontal cortex (DLPFC) seed-to-voxel functional connectivity analysis was conducted to evaluate the progressive neural alterations specific to PD-pRBD+ compared with PD-pRBD− over time. Furthermore, relationships between these alterations and neuropsychological performance were examined. Compared with patients with PD-pRBD−, patients with PD-pRBD+ initially exhibited connectivity deficits between the left DLPFC and the medial frontopolar cortex. Moreover, these patients further exhibited disrupted DLPFC connectivity in the lateral frontopolar cortex at the 3-year follow-up evaluation. Correlation analysis revealed that connectivity between the left DLPFC and frontopolar cortex was positively related to executive function in PD-pRBD+ after adjusting for nuisance variables. Progressive prefrontal cortex dysfunction associated with RBD in early PD may provide an effective subtype-specific biomarker of neurodegenerative progression, which may shed light on the neuropathological mechanisms underlying the clinical heterogeneity of this disease.

Classification of Cognitive Impairment and Healthy Controls Based on Transcranial Magnetic Stimulation Evoked Potentials

Backgrounds: Nowadays, risks of Cognitive Impairment (CI) [highly suspected Alzheimer's disease (AD) in this study] threaten the quality of life for more older adults as the population ages. The emergence of Transcranial Magnetic Stimulation-Electroencephalogram (TMS-EEG) enables noninvasive neurophysiological investi-gation of the human cortex, which might be potentially used for CI detection.Objectives: The aim of this study is to explore whether the spatiotemporal features of TMS Evoked Potentials (TEPs) could classify CI from healthy controls (HC).Methods: Twenty-one patients with CI and 22 HC underwent a single-pulse TMS-EEG stimulus in which the pulses were delivered to the left dorsolateral prefrontal cortex (left DLPFC). After preprocessing, seven regions of interest (ROIs) and two most reliable TEPs' components: N100 and P200 were selected. Next, seven simple and interpretable linear features of TEPs were extracted for each region, three common machine learning algorithms including Support Vector Machine (SVM), Random Forest (RF), and K-Nearest Neighbor (KNN) were used to detect CI. Meanwhile, data augmentation and voting strategy were used for a more robust model. Finally, the performance differences of features in classifiers and their contributions were investigated.Results: 1. In the time domain, the features of N100 had the best performance in the SVM classifier, with an accuracy of 88.37%. 2. In the aspect of spatiality, the features of the right frontal region and left parietal region had the best performance in the SVM classifier, with an accuracy of 83.72%. 3. The Local Mean Field Power (LMFP), Average Value (AVG), Latency and Amplitude contributed most in classification.Conclusions: The TEPs induced by TMS over the left DLPFC has significant differences spatially and temporally between CI and HC. Machine learning based on the spatiotemporal features of TEPs have the ability to separate the CI and HC which suggest that TEPs has potential as non-invasive biomarkers for CI diagnosis.

Enriched Rehabilitation Improves Gait Disorder and Cognitive Function in Parkinson’s Disease: A Randomized Clinical Trial

Background: Studies on non-pharmacological strategies for improving gait performance and cognition in Parkinson’s disease (PD) are of great significance. We aimed to investigate the effect of and mechanism underlying enriched rehabilitation as a potentially effective strategy for improving gait performance and cognition in early-stage PD.Methods: Forty participants with early-stage PD were randomly assigned to receive 12 weeks (2 h/day, 6 days/week) of enriched rehabilitation (ER; n = 20; mean age, 66.14 ± 4.15 years; 45% men) or conventional rehabilitation (CR; n = 20; mean age 65.32 ± 4.23 years; 50% men). In addition, 20 age-matched healthy volunteers were enrolled as a control (HC) group. We assessed the general motor function using the Unified PD Rating Scale—Part III (UPDRS-III) and gait performance during single-task (ST) and dual-task (DT) conditions pre- and post-intervention. Cognitive function assessments included the Montreal Cognitive Assessment (MoCA), the Symbol Digit Modalities Test (SDMT), and the Trail Making Test (TMT), which were conducted pre- and post-intervention. We also investigated alteration in positive resting-state functional connectivity (RSFC) of the left dorsolateral prefrontal cortex (DLPFC) in participants with PD, mediated by ER, using functional magnetic resonance imaging (fMRI).Results: Compared with the HC group, PD participants in both ER and CR groups performed consistently poorer on cognitive and motor assessments. Significant improvements were observed in general motor function as assessed by the UPDRS-III in both ER and CR groups post-intervention. However, only the ER group showed improvements in gait parameters under ST and DT conditions post-intervention. Moreover, ER had a significant effect on cognition, which was reflected in increased MoCA, SDMT, and TMT scores post-intervention. MoCA, SDMT, and TMT scores were significantly different between ER and CR groups post-intervention. The RSFC analysis showed strengthened positive functional connectivity between the left DLPFC and other brain areas including the left insula and left inferior frontal gyrus (LIFG) post-ER.Conclusion: Our findings indicated that ER could serve as a potentially effective therapy for early-stage PD for improving gait performance and cognitive function. The underlying mechanism based on fMRI involved strengthened RSFC between the left DLPFC and other brain areas (e.g., the left insula and LIFG).

The Role of Left Dorsolateral Prefrontal Cortices in Aesthetic Valuation

As discussed in both the original study and the current chapter, the dorsolateral prefrontal cortex (DLPFC) is a required neural player in the aesthetic appraisal and a basic stage of the aesthetic experience. As the distinct activation that the authors found in the neuroimaging study occurred when participants rated as beautiful natural, artistic, and decorative stimuli, we concluded that left DLPFC responded to aesthetic qualities in general and not to specific artistic qualities. More recent studies indicate that the function of the LPFC in relation to aesthetics may be to exercise cognitive control to direct attention with a proper aesthetic orientation. Other studies suggest that LPFC is part of a frontal “evaluative” network which supports an analysis of emotional response and personal relevance. Specifically, left DLPFC seems to affect the evaluation of different images, disengaging from a habitual mode of identifying objects in order to adopt an aesthetic perspective.

Non-invasive Brain Stimulation Modulates GABAergic Activity in Neurofibromatosis 1

Neurofibromatosis 1 (NF1) is a single-gene disorder associated with cognitive phenotypes common to neurodevelopmental conditions such as Autism Spectrum Disorder (ASD) & Attention Deficit Hyperactivity Disorder (ADHD). GABAergic dysregulation underlies working memory impairments seen in NF1. This mechanistic experimental study investigates whether application of anodal transcranial direct current stimulation (atDCS) can modulate GABA and working memory in NF1. 31 adolescents with NF1 were recruited to this single-blind sham-controlled cross-over randomized trial. Active or sham tDCS was applied to the left Dorsolateral Prefrontal Cortex (DLPFC) and Magnetic Resonance Spectroscopy was collected before and after intervention in the left DLPFC and occipital cortex. Higher baseline GABA in the left DLPFC was associated with faster response times (RT) on baseline working memory measures. AtDCS was seen to significantly reduced GABA as compared to sham stimulation in the left DLPFC. There was no effect of atDCS on Glutamate/glutamine (Glx) in the left DLPFC or on GABA/Glx in the occipital cortex. This first such study in adolescents with NF1, showed that atDCS modulates inhibitory activity in the DLPFC. Given the strong evidence linking GABA abnormalities to cognitive deficits across neurodevelopmental conditions such as ASD, modulation of GABA using atDCS offers a promising therapeutic approach.ClinicalTrials.gov Identifier: NCT0499142. Registered 05/08/2021; retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT04991428

Effects of Transcranial Direct Current Stimulation Treatment for Anorexia Nervosa

Background: Anorexia nervosa (AN) is a life-threatening illness with poor treatment outcomes. Although transcranial direct current stimulation (tDCS) is a promising non-invasive brain stimulation method, its effect in patients with AN remains unclear.Objective: This study investigated changes in maladaptive eating behavior, body mass index (BMI), and depression after 10 sessions of anodal tDCS over the left dorsolateral prefrontal cortex (DLPFC).Methods: In this double-blind, randomized controlled trial, 43 inpatients with AN were divided to receive either active (n = 22) or sham (n = 21) tDCS over the left DLPFC (anode F3/cathode Fp2, 2 mA for 30 min). All patients filled the Eating Disorder Examination Questionnaire (EDE-Q) and Zung Self-Rating Depression Scale (ZUNG), and their BMI was measured. These values were obtained repeatedly in four stages: (1) before tDCS treatment, (2) after tDCS treatment, (3) in the follow-up after 2 weeks, and (4) in the follow-up after 4 weeks.Results: Primary outcomes (EDE-Q) based on the ANOVA results do not show any between-group differences either after the active part of the study or in the follow-up. Secondary analysis reveals a reduction in some items of EDE-Q. Compared with sham tDCS, active tDCS significantly improved self-evaluation based on body shape (p < 0.05) and significantly decreased the need of excessive control over calorie intake (p < 0.05) in the 4-week follow-up. However, the results do not survive multiple comparison correction. In both sham and active groups, the BMI values improved, albeit not significantly.Conclusion: We did not observe a significant effect of tDCS over the left DLPFC on complex psychopathology and weight recovery in patients with AN. tDCS reduced the need to follow specific dietary rules and improved body image evaluation in patients with AN. Tests with a larger sample and different positions of electrodes are needed.Clinical Trial Registration:www.ClinicalTrials.gov, identifier: NCT03273205.

Stimulation of the left dorsolateral prefrontal cortex with slow rTMS enhances verbal memory formation

Encoding of episodic memories relies on stimulus-specific information processing and involves the left prefrontal cortex. We here present an incidental finding from a simultaneous EEG-TMS experiment as well as a replication of this unexpected effect. Our results reveal that stimulating the left dorsolateral prefrontal cortex (DLPFC) with slow repetitive transcranial magnetic stimulation (rTMS) leads to enhanced word memory performance. A total of 40 healthy human participants engaged in a list learning paradigm. Half of the participants (N = 20) received 1 Hz rTMS to the left DLPFC, while the other half (N = 20) received 1 Hz rTMS to the vertex and served as a control group. Participants receiving left DLPFC stimulation demonstrated enhanced memory performance compared to the control group. This effect was replicated in a within-subjects experiment where 24 participants received 1 Hz rTMS to the left DLPFC and vertex. In this second experiment, DLPFC stimulation also induced better memory performance compared to vertex stimulation. In addition to these behavioural effects, we found that 1 Hz rTMS to DLPFC induced stronger beta power modulation in posterior areas, a state that is known to be beneficial for memory encoding. Further analysis indicated that beta modulations did not have an oscillatory origin. Instead, the observed beta modulations were a result of a spectral tilt, suggesting inhibition of these parietal regions. These results show that applying 1 Hz rTMS to DLPFC, an area involved in episodic memory formation, improves memory performance via modulating neural activity in parietal regions.

Anodal tDCS augments and preserves working memory beyond time-on-task deficits

Transcranial direct current stimulation (tDCS) of the left dorsolateral prefrontal cortex (DLPFC) has been shown to promote working memory (WM), however, its efficacy against time-on-task-related performance decline and associated cognitive fatigue remains uncertain. This study examined the impact of anodal tDCS of the left DLPFC on performance during a fatiguing visuospatial WM test. We adopted a repeated measures design, where 32 healthy adults (16 female), underwent anodal, control and sham tDCS on separate days. They completed an hour long two-back test, with stimulation intensity, onset, and duration set at 1 mA, at the 20th minute for 10 minutes respectively. Task performance, subjective responses, and heart rate variability (HRV) were captured during the experiment. Anodal tDCS substantially improved WM relative to sham tDCS and control in both sexes. These benefits lasted beyond the stimulation interval, and were unique across performance measures. However, no perceptual changes in subjective effort or fatigue levels were noted between conditions, although participants reported greater discomfort during stimulation. While mood and sleepiness changed with time-on-task, reflecting fatigue, these were largely similar across conditions. HRV increased under anodal tDCS and control, and plateaued under sham tDCS. We found that short duration anodal tDCS at 1 mA was an effective countermeasure to time-on-task deficits during a visuospatial two-back task, with enhancement and preservation of WM capacity. However, these improvements were not available at a perceptual level. Therefore, wider investigations are necessary to determine “how” such solutions will be operationalized in the field, especially within human-centered systems.