Multisensory mechanisms of gait and balance in Parkinson's disease: an integrative review.

Understanding the neural underpinning of human gait and balance is one of the most pertinent challenges for 21st-century translational neuroscience due to the profound impact that falls and mobility disturbances have on our aging population. Posture and gait control does not happen automatically, as previously believed, but rather requires continuous involvement of central nervous mechanisms. To effectively exert control over the body, the brain must integrate multiple streams of sensory information, including visual, vestibular, and somatosensory signals. The mechanisms which underpin the integration of these multisensory signals are the principal topic of the present work. Existing multisensory integration theories focus on how failure of cognitive processes thought to be involved in multisensory integration leads to falls in older adults. Insufficient emphasis, however, has been placed on specific contributions of individual sensory modalities to multisensory integration processes and cross-modal interactions that occur between the sensory modalities in relation to gait and balance. In the present work, we review the contributions of somatosensory, visual, and vestibular modalities, along with their multisensory intersections to gait and balance in older adults and patients with Parkinson's disease. We also review evidence of vestibular contributions to multisensory temporal binding windows, previously shown to be highly pertinent to fall risk in older adults. Lastly, we relate multisensory vestibular mechanisms to potential neural substrates, both at the level of neurobiology (concerning positron emission tomography imaging) and at the level of electrophysiology (concerning electroencephalography). We hope that this integrative review, drawing influence across multiple subdisciplines of neuroscience, paves the way for novel research directions and therapeutic neuromodulatory approaches, to improve the lives of older adults and patients with neurodegenerative diseases.

Beta-Gamma Phase-Amplitude Coupling as a Non-Invasive Biomarker for Parkinson's Disease: Insights from Electroencephalography Studies.

Phase-amplitude coupling (PAC) describes the interaction of two separate frequencies in which the lower frequency phase acts as a carrier frequency of the higher frequency amplitude. It is a means of carrying integrated streams of information between micro- and macroscale systems in the brain, allowing for coordinated activity of separate brain regions. A beta-gamma PAC increase over the sensorimotor cortex has been observed consistently in people with Parkinson's disease (PD). Its cause is attributed to neural entrainment in the basal ganglia, caused by pathological degeneration characteristic of PD. Disruptions in this phenomenon in PD patients have been observed in the resting state as well as during movement recordings and have reliably distinguished patients from healthy participants. The changes can be detected non-invasively with the electroencephalogram (EEG). They correspond to the severity of the motor symptoms and the medication status of people with PD. Furthermore, a medication-induced decrease in PAC in PD correlates with the alleviation of motor symptoms measured by assessment scales. A beta-gamma PAC increase has, therefore, been explored as a possible means of quantifying motor pathology in PD. The application of this parameter to closed-loop deep brain stimulation could serve as a self-adaptation measure of such treatment, responding to fluctuations of motor symptom severity in PD. Furthermore, phase-dependent stimulation provides a new precise method for modulating PAC increases in the cortex. This review offers a comprehensive synthesis of the current EEG-based evidence on PAC fluctuations in PD, explores the potential practical utility of this biomarker, and provides recommendations for future research.

Basal forebrain integrity, cholinergic innervation and cognition in idiopathic Parkinson's disease.

Most individuals with Parkinson's disease experience cognitive decline. Mounting evidence suggests this is partially caused by cholinergic denervation due to α-synuclein pathology in the cholinergic basal forebrain. Alpha-synuclein deposition causes inflammation, which can be measured with free water fraction, a diffusion MRI-derived metric of extracellular water. Prior studies have shown an association between basal forebrain integrity and cognition, cholinergic levels and cognition, and basal forebrain volume and acetylcholine, but no study has directly investigated whether basal forebrain physiology mediates the relationship between acetylcholine and cognition in Parkinson's disease. We investigated the relationship between these variables in a cross-sectional analysis of 101 individuals with Parkinson's disease. Cholinergic levels were measured using fluorine-18 fluoroethoxybenzovesamicol (18F-FEOBV) PET imaging. Cholinergic innervation regions of interest included the medial, lateral capsular and lateral perisylvian regions and the hippocampus. Brain volume and free water fraction were quantified using T1 and diffusion MRI, respectively. Cognitive measures included composites of attention/working memory, executive function, immediate memory and delayed memory. Data were entered into parallel mediation analyses with the cholinergic projection areas as predictors, cholinergic basal forebrain volume and free water fraction as mediators and each cognitive domain as outcomes. All mediation analyses controlled for age, years of education, levodopa equivalency dose and systolic blood pressure. The basal forebrain integrity metrics fully mediated the relationship between lateral capsular and lateral perisylvian acetylcholine and attention/working memory, and partially mediated the relationship between medial acetylcholine and attention/working memory. Basal forebrain integrity metrics fully mediated the relationship between medial, lateral capsular and lateral perisylvian acetylcholine and free water fraction. For all mediations in attention/working memory and executive function, the free water mediation was significant, while the volume mediation was not. The basal forebrain integrity metrics fully mediated the relationship between hippocampal acetylcholine and delayed memory and partially mediated the relationship between lateral capsular and lateral perisylvian acetylcholine and delayed memory. The volume mediation was significant for the hippocampal and lateral perisylvian models, while free water fraction was not. Free water fraction in the cholinergic basal forebrain mediated the relationship between acetylcholine and attention/working memory and executive function, while cholinergic basal forebrain volume mediated the relationship between acetylcholine in temporal regions in memory. These findings suggest that these two metrics reflect different stages of neurodegenerative processes and add additional evidence for a relationship between pathology in the basal forebrain, acetylcholine denervation and cognitive decline in Parkinson's disease.

GABAA Receptor Benzodiazepine Binding Sites and Motor Impairments in Parkinson's Disease.

Flumazenil is an allosteric modulator of the γ-aminobutyric acid-A receptor (GABAAR) benzodiazepine binding site that could normalize neuronal signaling and improve motor impairments in Parkinson's disease (PD). Little is known about how regional GABAAR availability affects motor symptoms. We investigated the relationship between regional availability of GABAAR benzodiazepine binding sites and motor impairments in PD. Methods: A total of 11 Patients with PD (males; mean age 69.0 ± 4.6 years; Hoehn and Yahr stages 2-3) underwent [11C]flumazenil GABAAR benzodiazepine binding site and [11C]dihydrotetrabenazine vesicular monoamine transporter type-2 (VMAT2) PET imaging and clinical assessment. Stepwise regression analysis was used to predict regional cerebral correlates of the four cardinal UPDRS motor scores using cortical, striatal, thalamic, and cerebellar flumazenil binding estimates. Thalamic GABAAR availability was selectively associated with axial motor scores (R2 = 0.55, F = 11.0, ß = -6.4, p = 0.0009). Multi-ligand analysis demonstrated significant axial motor predictor effects by both thalamic GABAAR availability (R2 = 0.47, ß = -5.2, F = 7.2, p = 0.028) and striatal VMAT2 binding (R2 = 0.30, ß = -3.9, F = 9.1, p = 0.019; total model: R2 = 0.77, F = 11.9, p = 0.0056). Post hoc analysis demonstrated that thalamic [11C]methyl-4-piperidinyl propionate cholinesterase PET and K1 flow delivery findings were not significant confounders. Findings suggest that reduced thalamic GABAAR availability correlates with worsened axial motor impairments in PD, independent of nigrostriatal degeneration. These findings may augur novel non-dopaminergic approaches to treating axial motor impairments in PD.

Challenges and innovations in brain PET analysis of neurodegenerative disorders: a mini-review on partial volume effects, small brain region studies, and reference region selection.

Positron Emission Tomography (PET) brain imaging is increasingly utilized in clinical and research settings due to its unique ability to study biological processes and subtle changes in living subjects. However, PET imaging is not without its limitations. Currently, bias introduced by partial volume effect (PVE) and poor signal-to-noise ratios of some radiotracers can hamper accurate quantification. Technological advancements like ultra-high-resolution scanners and improvements in radiochemistry are on the horizon to address these challenges. This will enable the study of smaller brain regions and may require more sophisticated methods (e.g., data-driven approaches like unsupervised clustering) for reference region selection and to improve quantification accuracy. This review delves into some of these critical aspects of PET molecular imaging and offers suggested strategies for improvement. This will be illustrated by showing examples for dopaminergic and cholinergic nerve terminal ligands.