Neuroenergetic alterations in neurodegenerative diseases: A systematic review and meta-analysis of in vivo31P-MRS studies.

Phosphorus magnetic resonance spectroscopy (31P-MRS) is applied for non-invasive studies of neuroenergetic metabolism in neurodegenerative diseases. However, the findings are inconsistent and have not yet been tested in meta-analyses. To address this gap, we performed a systematic review of 29 studies and conducted meta-analyses for 9 studies on Alzheimer's disease (AD, n = 140 patients), 9 studies on Parkinson's disease (PD, n = 183 patients), 3 studies on Progressive Supranuclear Palsy (PSP, n = 42 patients), and 2 studies on Multiple System Atrophy (MSA, n = 24 patients). Compared to controls, AD patients had a higher ratio of phosphomonoesters/phosphodiesters (PME/PDE) in the frontal lobe (MD = 0.049, p = 0.0003); PD patients showed decreases in PME/PDE in the putamen (MD = -0.050, p = 0.023) and adenosine triphosphate/inorganic phosphate (ATP/Pi) in the midbrain (MD = -0.274, p = 0.002); PSP patients presented increased phosphocreatine (PCr)/Pi in the basal ganglia (MD = 0.556, p = 0.030) and adenosine diphosphate (ADP)/Pi in the occipital lobe (MD = 0.005, p = 0.009); no significant effects were observed in MSA. Here, our review underlines the importance of 31P-MRS in the characterization of distinct neuroenergetic changes and its potential to improve the diagnosis and follow-up of neurodegenerative diseases.

Repetitive Subconcussive Head Impacts in Sports and Their Impact on Brain Anatomy and Function: A Systematic Review.

Repetitive subconcussive head impacts occur regularly in sports. However, the exact relationship between their biomechanical properties and their consequences on brain structure and function has not been clarified yet. We therefore reviewed prospective cohort studies that objectively reported the biomechanical characteristics of repetitive subconcussive head impacts and their impact on brain anatomy and function. Only studies with a pre- to post-measurement design were included. Twenty-four studies met the inclusion criteria. Structural white matter alterations, such as reduced fractional anisotropy and an increase in mean diffusivity values, seem to be evident in athletes exposed to repetitive subconcussive head impacts exceeding 10 g. Such changes are observable after only one season of play. Furthermore, a dose-response relationship exists between white matter abnormalities and the total number of subconcussive head impacts. However, functional changes after repetitive subconcussive head impacts remain inconclusive. We therefore conclude that repetitive subconcussive head impacts induce structural changes, but thus far without overt functional changes.

Success rates of intensive aphasia therapy: real-world data from 448 patients between 2003 and 2020.

BACKGROUND: Aphasia is a devastating consequence after stroke, affecting millions of patients each year. Studies have shown that intensive speech and language therapy (SLT) is effective in the chronic phase of aphasia. Leveraging a large single-center cohort of persons with aphasia (PWA) including patients also in the subacute phase, we assessed treatment effects of intensive aphasia therapy in a real-world setting. METHODS: Data were collected at the Aachen aphasia ward in Germany between 2003 and 2020. Immediate treatment responses across different language domains were assessed with the Aachen Aphasia Test (AAT) using single-case psychometrics, conducted before and after 6-7 weeks of intensive SLT (10 h per week, median (IQR) dosage = 68 (61-76)). We adjusted for spontaneous recovery in subacute patients. Differential treatment effects between subgroups of chronicity and predictors of therapy response were investigated. RESULTS: A total of 448 PWA were included (29% female, median (IQR) age = 54 (46-62) years, median (IQR) time post-onset = 11 (6-20) months) with 12% in the early subacute, 15% in the late subacute and 74% in the chronic phase of aphasia. The immediate responder rate was 59%. Significant improvements in all AAT subtests und subscales were observed hinting at broad effectiveness across language domains. The degree of therapy-induced improvement did not differ between the chronicity groups. Time post-onset, dosage of therapy and aphasia severity at the beginning of treatment were predictors of immediate treatment response. DISCUSSION: Intensive therapy protocols for aphasia after stroke are yielding substantial responder rates in a routine clinical setting including a wide range of patients.

Characteristic functional connectome related to Post-COVID-19 syndrome.

Post-COVID-19 syndrome is a serious complication following SARS-CoV-2 infection, characterized primarily by fatigue and cognitive complaints. Although first metabolic and structural imaging alterations in Post-COVID-19 syndrome have been identified, their functional consequences remain unknown. Thus, we explored the impact of Post-COVID-19 syndrome on the functional connectome of the brain providing a deeper understanding of pathophysiological mechanisms. In a cross-sectional observational study, resting-state functional magnetic resonance imaging data of 66 patients with Post-COVID-19 syndrome after mild infection (mean age 42.3 years, 57 female) and 57 healthy controls (mean age 42.1 years, 38 female) with a mean time of seven months after acute COVID-19 were analysed using a graph theoretical approach. Network features were quantified using measures including mean distance, nodal degree, betweenness and Katz centrality, and compared between both groups. Graph measures were correlated with clinical measures quantifying fatigue, cognitive function, affective symptoms and sleep disturbances. Alterations were mainly found in the brainstem, olfactory cortex, cingulate cortex, thalamus and cerebellum on average seven months after SARS-CoV-2 infection. Additionally, strong correlations between fatigue severity, cognitive functioning and daytime sleepiness from clinical scales and graph measures were observed. Our study confirms functional relevance of brain imaging changes in Post-COVID-19 syndrome as mediating factors for persistent symptoms and improves our pathophysiological understanding.

Perception of robotic actions and the influence of gender.

In our society interaction with robots is becoming more and more frequent since robots are not only used in the industry, but increasingly often in assistance and in health system. Perception of robots and their movements is crucial for their acceptance. Here we shortly review basic mechanisms of perception of actions, and then of perception of robotic and human movements. The literature demonstrates that there are commonalities, but also differences in the perception of human and robotic movements. Especially interesting are biologic gender differences in the perception of robotic movements. The results show that males seem to be more sensitive to the differences between robotic and anthropomorphic movements, whereas females seem not to perceive such differences. However, females transfer more anthropomorphic features to robotic movements. While looking at the brain activation during perception of humanoid and robotic movements in different genders one can conclude that different strategies are used; female seem to analyse robotic movements online, while male seem to use previous knowledge from interaction with robots. Further research is needed to specify more such gender differences.

Single dose creatine improves cognitive performance and induces changes in cerebral high energy phosphates during sleep deprivation.

The inverse effects of creatine supplementation and sleep deprivation on high energy phosphates, neural creatine, and cognitive performances suggest that creatine is a suitable candidate for reducing the negative effects of sleep deprivation. With this, the main obstacle is the limited exogenous uptake by the central nervous system (CNS), making creatine only effective over a long-term diet of weeks. Thus far, only repeated dosing of creatine over weeks has been studied, yielding detectable changes in CNS levels. Based on the hypothesis that a high extracellular creatine availability and increased intracellular energy consumption will temporarily increase the central creatine uptake, subjects were orally administered a high single dose of creatinemonohydrate (0.35 g/kg) while performing cognitive tests during sleep deprivation. Two consecutive 31P-MRS scans, 1H-MRS, and cognitive tests were performed each at evening baseline, 3, 5.5, and 7.5 h after single dose creatine (0.35 g/kg) or placebo during sub-total 21 h sleep deprivation (SD). Our results show that creatine induces changes in PCr/Pi, ATP, tCr/tNAA, prevents a drop in pH level, and improves cognitive performance and processing speed. These outcomes suggest that a high single dose of creatine can partially reverse metabolic alterations and fatigue-related cognitive deterioration.

Neural correlates of virtual reality-based attention training: An fMRI study.

THEORETICAL BACKGROUND: Virtual Reality technology is increasingly used in attention rehabilitation for functional training purposes. However, the neural mechanisms by which Virtual Reality can affect attentional functioning are still unclear. The current study's objective is to examine the effects of stereoscopic vs. monoscopic presentation on neural processing during a visual attention task. METHOD: Thirty-two healthy participants performed a visual attention task in an immersive virtual environment that was displayed via MR-compatible video goggles in an MRI scanner. The paradigm altered between trials that required active engagement with the task and mere observation trials. Furthermore, the form of binocular presentation switched between monoscopic and stereoscopic presentation. RESULTS: Analyses yielded evidence for increased activation in stereoscopic compared to monoscopic trials in the tertiary visual cortex area V3A as well as elevated activation in the dorsal attention network when engaging in the attention task. An additional ROI analysis of area V3A revealed significantly lower attentional engagement costs in stereoscopic conditions. DISCUSSION: Results support previous findings suggesting that V3A is involved in binocular depth perception. Furthermore, heightened activation in V3A following stereoscopic presentation seemed to facilitate attentional engagement with the task. Considering that V3A is the origin of the dorso-dorsal, ventro-dorsal, and ventral visual processing pathways, we regard it as a gating area that decides which kind of visual perception is processed.

Parietal control of hand movement.

The parietal lobe has been implicated in the sensorimotor control and integration that supports the skillful use of our hands to reach for, grasp, and manipulate objects in the environment. This area is involved in several circuits within the classic subdivisions of the dorsal stream. Recently, the dorsal stream has been further divided into a "dorso-dorsal" and a "ventro-dorsal" streams. The ventro-dorsal stream is regarded as functionally linked to object manipulation. The dorso-dorsal stream is proposed to subserve reaching and online control of actions. Affordances indicate action possibilities characterized by object properties the environment provides. Affordances are likely represented by the dorsal stream. They code structural object properties that can elicit actions. A further subdivision of affordances into "stable" and "variable" allows an understanding of the neuronal mechanisms underlying object manipulation. Whereas stable affordances emerge from slow processing of visual information based on knowledge of object properties from previous experiences and object interaction, variable affordances emerge from fast online processing of visual information during actual object interaction, within a changing environment. The relevance of the dorsal stream subdivisions in this context is that the dorso-dorsal stream is associated with coding of variable affordances, while that of the dorso-ventral stream is implicated in action representations elicited by stable affordances. A greater interaction between these and ventral stream perceptual and semantic representations allows the parietal control of hand movement. An understanding of these networks is likely to underlie recovery from complex deficits described in limb apraxias.

Neural Correlates of Oral Stereognosis-An fMRI Study.

Oral stereognosis is the ability to recognize, discriminate and localize a bolus in the oral cavity. Clinical observation indicates deficits in oral stereognosis in patients with vascular or neurodegenerative diseases particularly affecting the parietal lobes. However, the precise neural representation of oral stereognosis remains unclear whereas the neural network of manual stereognosis has already been identified. We hypothesize that oral and manual stereognosis share common neuronal substrates whilst also showing somatotopic distribution. Functional magnetic resonance images (fMRI; Siemens Prisma 3 T) from 20 healthy right-handed participants (11 female; mean age 25.7 years) using a cross-modal task of oral and manual spatial object manipulation were acquired. Data were analyzed using FSL software using a block design and standard analytical and statistical procedures. A conjunction analysis targeted the common neuronal substrate for stereognosis. Activations associated with manual and oral stereognosis were found in partially overlapping fronto-parietal networks in a somatotopic fashion, where oral stereognosis is located caudally from manual stereognosis. A significant overlap was seen in the left anterior intraparietal sulcus. Additionally, cerebellar activations were shown particularly for the oral condition. Spatial arrangement of shaped boli in the oral cavity is associated with neuronal activity in fronto-parietal networks and the cerebellum. These findings have significant implications for clinical diagnostics and management of patients with lesions or atrophy in parietal lobule (e.g. Alzheimer's disease, stroke). More studies are required to investigate the clinical effect of damage to these areas, such as loss of oral stereognosis or an impaired oral phase.

Limb Apraxias: The Influence of Higher Order Perceptual and Semantic Deficits in Motor Recovery After Stroke.

Stroke is a leading cause of disability worldwide. Limb apraxia is a group of higher order motor disorders associated with greater disability and dependence after stroke. Original neuropsychology studies distinguished separate brain pathways involved in perception and action, known as the dual stream hypothesis. This framework has allowed a better understanding of the deficits identified in Limb Apraxia. In this review, we propose a hierarchical organization of this disorder, in which a distinction can be made between several visuomotor pathways that lead to purposeful actions. Based on this, executive apraxias (such as limb kinetic apraxia) cause deficits in executing fine motor hand skills, and intermediate apraxias (such as optic ataxia and tactile apraxia) cause deficits in reaching to grasp and manipulating objects in space. These disorders usually affect the contralesional limb. A further set of disorders collectively known as limb apraxias include deficits in gesture imitation, pantomime, gesture recognition, and object use. These deficits are due to deficits in integrating perceptual and semantic information to generate complex movements. Limb apraxias are usually caused by left-hemisphere lesions in right-handed stroke patients, affecting both limbs. The anterior- to posterior-axis of brain areas are disrupted depending on the increasing involvement of perceptual and semantic processes with each condition. Lower-level executive apraxias are linked to lesions in the frontal lobe and the basal ganglia, while intermediate apraxias are linked to lesions in dorso-dorsal subdivisions of the dorsal fronto-parietal networks. Limb apraxias can be caused by lesions in both dorsal and ventral subdivisions including the ventro-dorsal stream and a third visuomotor pathway, involved in body schema and social cognition. Rehabilitation of these disorders with behavioral therapies has aimed to either restore perceptuo-semantic deficits or compensate to overcome these deficits. Further studies are required to better stratify patients, using modern neurophysiology and neuroimaging techniques, to provide targeted and personalized therapies for these disorders in the future.

Increasing striatal dopamine release through repeated bouts of theta burst transcranial magnetic stimulation of the left dorsolateral prefrontal cortex. A 18F-desmethoxyfallypride positron emission tomography study.

Introduction: Transcranial Magnetic Stimulation (TMS) can modulate fronto-striatal connectivity in the human brain. Here Positron Emission Tomography (PET) and neuro-navigated TMS were combined to investigate the dynamics of the fronto-striatal connectivity in the human brain. Employing 18F-DesmethoxyFallypride (DMFP) - a Dopamine receptor-antagonist - the release of endogenous dopamine in the striatum in response to time-spaced repeated bouts of excitatory, intermittent theta burst stimulation (iTBS) of the Left-Dorsolateral Prefrontal Cortex (L-DLPFC) was measured. Methods: 23 healthy participants underwent two PET sessions, each one with four blocks of iTBS separated by 30 minutes: sham (control) and verum (90% of individual resting motor threshold). Receptor Binding Ratios were collected for sham and verum sessions across 37 time frames (about 130 minutes) in striatal sub-regions (Caudate nucleus and Putamen). Results: Verum iTBS increased the dopamine release in striatal sub-regions, relative to sham iTBS. Dopamine levels in the verum session increased progressively across the time frames until frame number 28 (approximately 85 minutes after the start of the session and after three iTBS bouts) and then essentially remained unchanged until the end of the session. Conclusion: Results suggest that the short-timed iTBS protocol performed in time-spaced blocks can effectively induce a dynamic dose dependent increase in dopaminergic fronto-striatal connectivity. This scheme could provide an alternative to unpleasant and distressing, long stimulation protocols in experimental and therapeutic settings. Specifically, it was demonstrated that three repeated bouts of iTBS, spaced by short intervals, achieve larger effects than one single stimulation. This finding has implications for the planning of therapeutic interventions, for example, treatment of major depression.

Anthropomorphic or non-anthropomorphic? Effects of biological sex in observation of actions in a digital human model and a gantry robot model.

Robots are ever more relevant for everyday life, such as healthcare or rehabilitation, as well as for modern industrial environment. One important issue in this context is the way we perceive robots and their actions. From our previous study, evidence exists that sex can affect the way people perceive certain robot's actions. In our fMRI study, we analyzed brain activations of female and male participants, while they observed anthropomorphic and robotic movements performed by a human or a robot model. While lying in the scanner, participants rated the perceived level of anthropomorphic and robotic likeness of movements in the two models. The observation of the human model and the anthropomorphic movements similarly activated the biological motion coding areas in posterior temporal and parietal areas. The observation of the robot model activated predominantly areas of the ventral stream, whereas the observation of robotic movements activated predominantly the primary and higher order motor areas. To note, this later activation originated mainly from female participants, whereas male participants activated, in both robot model and robotic movements contrasts, areas in the posterior parietal cortex. Accordingly, the general contrast of sex suggests that men tend to use the ventro-dorsal stream most plausibly to rely on available previous knowledge to analyze the movements, whereas female participants use the dorso-dorsal and the ventral streams to analyze online the differences between the movement types and between the different models. The study is a first step toward the understanding of sex differences in the processing of anthropomorphic and robotic movements.

Preconditioning prefrontal connectivity using transcranial direct current stimulation and transcranial magnetic stimulation.

Transcranial direct current stimulation (tDCS) and transcranial magnetic stimulation (TMS) have been shown to modulate functional connectivity. Their specific effects seem to be dependent on the pre-existing neuronal state. We aimed to precondition frontal networks using tDCS and subsequently stimulate the left dorsolateral prefrontal cortex (lDLPFC) using TMS. Thirty healthy participants underwent excitatory, inhibitory, or sham tDCS for 10 min, as well as an excitatory intermittent theta-burst (iTBS) protocol (600 pulses, 190 s, 20 × 2-s trains), applied over the lDLPFC at 90% of the individual resting motor threshold. Functional connectivity was measured in three task-free resting state fMRI sessions, immediately before and after tDCS, as well as after iTBS. Testing the whole design did not yield any significant results. Analysis of the connectivity between the stimulation site and all other brain voxels, contrasting only the interaction effect between the experimental groups (excitatory vs. inhibitory) and the repeated measure (post-tDCS vs. post-TMS), revealed significantly affected voxels bilaterally in the anterior cingulate and paracingulate gyri, the caudate nuclei, the insula and operculum cortices, as well as the Heschl's gyrus. Post-hoc ROI-to-ROI analyses between the significant clusters and the striatum showed post-tDCS, temporo-parietal-to-striatal and temporo-parietal-to-fronto-cingulate differences between the anodal and cathodal tDCSgroup, as well as post-TMS, striatal-to-temporo-parietal differences between the anodal and cathodal groups and frontostriatal and interhemispheric temporo-parietal cathodal-sham group differences. Excitatory iTBS to a tDCS-inhibited lDLPFC thus yielded more robust functional connectivity to various areas as compared to excitatory iTBS to a tDCS-enhanced DLPFC. Even considering reduced statistical power due to low subject numbers, results demonstrate complex, whole-brain stimulation effects. They are possibly facilitated by cortical homeostatic control mechanisms and show the feasibility of using tDCS to modulate subsequent TMS effects. This proof-of-principle study might stimulate further research into the principle of preconditioning that might be useful in the development of protocols using DLPFC as a stimulation site for the treatment of depression.

Repeated Sub-Concussive Impacts and the Negative Effects of Contact Sports on Cognition and Brain Integrity.

Sports are yielding a wealth of benefits for cardiovascular fitness, for psychological resilience, and for cognition. The amount of practice, and the type of practiced sports, are of importance to obtain these benefits and avoid any side effects. This is especially important in the context of contact sports. Contact sports are not only known to be a major source of injuries of the musculoskeletal apparatus, they are also significantly related to concussion and sub-concussion. Sub-concussive head impacts accumulate throughout the active sports career, and thus can cause measurable deficits and changes to brain health. Emerging research in the area of cumulative sub-concussions in contact sports has revealed several associated markers of brain injury. For example, recent studies discovered that repeated headers in soccer not only cause measurable signs of cognitive impairment but are also related to a prolonged cortical silent period in transcranial magnetic stimulation measurements. Other cognitive and neuroimaging biomarkers are also pointing to adverse effects of heading. A range of fluid biomarkers completes the picture of cumulating effects of sub-concussive impacts. Those accumulating effects can cause significant cognitive impairment later in life of active contact sportswomen and men. The aim of this review is to highlight the current scientific evidence on the effects of repeated sub-concussive head impacts on contact sports athletes' brains, identify the areas in need of further investigation, highlight the potential of advanced neuroscientific methods, and comment on the steps governing bodies have made to address this issue. We conclude that there are indeed neural and biofluid markers that can help better understand the effects of repeated sub-concussive head impacts and that some aspects of contact sports should be redefined, especially in situations where sub-concussive impacts and concussions can be minimized.

The efficacy of a directed rhythmic-melodic voice training in the treatment of chronic non-fluent aphasia-Behavioral and imaging results.

The main objective of this study was to investigate the efficacy of a directed rhythmic-melodic voice training (SIPARI) compared to language therapy with the focus on improvement in expressive linguistic performance. 20 patients suffering from chronic non-fluent aphasia, allocated by coin tossing to either of the groups, participated in 32 single therapy sessions over a period of 4 months. Before and after therapy, independent testers performed a standardized language test (Aachener Aphasie Test). Behavioral assessments revealed that improvements of patients of the experimental group were clinically significant compared to those of the control group. These improvements concerned the description level articulation and prosody for spontaneous speech and the subtests repetition, naming, and comprehension. Based on these improvements, a significant increase in profile level (effect size (ES) = 2.028, p < 0.001) was assessed, an overall and clinically relevant measure of the severity of aphasia. Additional fMRI examinations yielded activation in the left superior frontal gyrus for the post-minus pre- therapy assessments only for participants of the experimental group. Since this brain region is reported to be particularly involved in executive processing, we assume that the directed procedure of the SIPARI treatment with regard to musical, linguistic, and cognitive function potentially holds the key for successful language rehabilitation. While our imaging results hint at a possible explanation for its efficacy, our behavioral results corroborate the efficacy of this therapy in the treatment of chronic non-fluent aphasia patients. DRKS00026730, 19.10.21, retrospectively registered https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00026730.

Long COVID-19: Objectifying most self-reported neurological symptoms.

OBJECTIVES: We aimed to objectify and compare persisting self-reported symptoms in initially hospitalized and non-hospitalized patients after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by applying clinical standardized measures. METHODS: We conducted a cross-sectional study of adult patients with confirmed SARS-CoV-2 infection including medical history, neurological examination, blood markers, neuropsychological testing, patient-reported outcome measures (PROMs), and brain magnetic resonance imaging (MRI). RESULTS: Fifty patients with persisting symptoms for at least 4 weeks were included and classified by initial hospitalization status. Median time from SARS-CoV-2 detection to investigation was 29.3 weeks (range 3.3-57.9). Although individual cognitive performance was generally within the normative range in both groups, mostly mild deficits were found in attention, executive functions, and memory. Hospitalized patients performed worse in global cognition, logical reasoning, and processes of verbal memory. In both groups, fatigue severity was associated with reduced performance in attention and psychomotor speed tasks (rs = -0.40, p < 0.05) and reduced quality of life (EQ5D, rs = 0.57, p < 0.001) and with more persisting symptoms (median 3 vs. 6, p < 0.01). PROMs identified fatigue, reduced sleep quality, and increased anxiety and depression in both groups but more pronounced in non-hospitalized patients. Brain MRI revealed microbleeds exclusively in hospitalized patients (n = 5). INTERPRETATION: Regardless of initial COVID-19 severity, an individuals' mental and physical health can be severely impaired in the long-term limitedly objectified by clinical standard diagnostic with abnormalities primarily found in hospitalized patients. This needs to be considered when planning rehabilitation therapies and should give rise to new biomarker research.

Respiratory function modulated during execution, observation, and imagination of walking via SII.

The Mirror Neurons System (MNS) consists of brain areas active during actions execution, as well as observation-imagination of the same actions. MNS represents a potential mechanism by which we understand other's action goals. We investigated MNS activation for legs actions, and its interaction with the autonomic nervous system. We performed a physiological and fMRI investigation on the common neural structures recruited during the execution, observation, and imagination of walking, and their effects on respiratory activity. Bilateral SMA were activated by all three tasks, suggesting that these areas are responsible for the core of the MNS effect for walking. Moreover, we observed in bilateral parietal opercula (OP1, secondary somatosensory cortex-SII) evidence of an MNS subtending walking execution-observation-imagination that also modulated the respiratory function. We suggest that SII, in modulating the vegetative response during motor activity but also during observation-imagination, consists of a re-enacting function which facilitates the understanding of motor actions.