Spinal inhibitory neurons degenerate before motor neurons and excitatory neurons in a mouse model of ALS.

Amyotrophic lateral sclerosis (ALS) is characterized by the progressive loss of somatic motor neurons. A major focus has been directed to motor neuron intrinsic properties as a cause for degeneration, while less attention has been given to the contribution of spinal interneurons. In the present work, we applied multiplexing detection of transcripts and machine learning-based image analysis to investigate the fate of multiple spinal interneuron populations during ALS progression in the SOD1G93A mouse model. The analysis showed that spinal inhibitory interneurons are affected early in the disease, before motor neuron death, and are characterized by a slow progressive degeneration, while excitatory interneurons are affected later with a steep progression. Moreover, we report differential vulnerability within inhibitory and excitatory subpopulations. Our study reveals a strong interneuron involvement in ALS development with interneuron specific degeneration. These observations point to differential involvement of diverse spinal neuronal circuits that eventually may be determining motor neuron degeneration.

Changes in Metabolism and Content of Chlorophyll in Common Duckweed (Lemna minor L.) Caused by Environmental Contamination with Fluorides.

The impact of fluorine on plants remains poorly understood. We examined duckweed growth in extracts of soil contaminated with fluorine leached from chicken manure. Additionally, fluorine levels were analyzed in fresh manure, outdoor-stored manure, and soil samples at varying distances from the manure pile. Fresh manure contained 37-48 mg F- × kg-1, while soil extracts contained 2.1 to 4.9 mg F- × kg-1. We evaluated the physiological effects of fluorine on duckweed cultured on soil extracts or in 50% Murashige-Skoog (MS) medium supplemented with fluorine concentrations matching those in soil samples (2.1 to 4.9 mg F- × L-1), as well as at 0, 4, and 210 mg × L-1. Duckweed exposed to fluorine displayed similar toxicity symptoms whether in soil extracts or supplemented medium. Fluoride at concentrations of 2.1 to 4.9 mg F- × L-1 reduced the intact chlorophyll content, binding the porphyrin ring at position 32 without affecting Mg2+. This reaction resulted in chlorophyll a absorption peak shifted towards shorter wavelengths and formation of a new band of the F--chlorophyll a complex at λ = 421 nm. Moreover, plants exposed to low concentrations of fluorine exhibited increased activities of aminolevulinic acid dehydratase and chlorophyllase, whereas the activities of both enzymes sharply declined when the fluoride concentration exceeded 4.9 mg × L-1. Consequently, fluorine damages chlorophyll a, disrupts the activity of chlorophyll-metabolizing enzymes, and diminishes the plant growth rate, even when the effects of these disruptions are too subtle to be discerned by the naked human eye.

Control of working memory by phase-amplitude coupling of human hippocampal neurons.

Retaining information in working memory is a demanding process that relies on cognitive control to protect memoranda-specific persistent activity from interference1,2. However, how cognitive control regulates working memory storage is unclear. Here we show that interactions of frontal control and hippocampal persistent activity are coordinated by theta-gamma phase-amplitude coupling (TG-PAC). We recorded single neurons in the human medial temporal and frontal lobe while patients maintained multiple items in their working memory. In the hippocampus, TG-PAC was indicative of working memory load and quality. We identified cells that selectively spiked during nonlinear interactions of theta phase and gamma amplitude. The spike timing of these PAC neurons was coordinated with frontal theta activity when cognitive control demand was high. By introducing noise correlations with persistently active neurons in the hippocampus, PAC neurons shaped the geometry of the population code. This led to higher-fidelity representations of working memory content that were associated with improved behaviour. Our results support a multicomponent architecture of working memory1,2, with frontal control managing maintenance of working memory content in storage-related areas3-5. Within this framework, hippocampal TG-PAC integrates cognitive control and working memory storage across brain areas, thereby suggesting a potential mechanism for top-down control over sensory-driven processes.

Dataset of human-single neuron activity during a Sternberg working memory task.

We present a dataset of 1809 single neurons recorded from the human medial temporal lobe (amygdala and hippocampus) and medial frontal lobe (anterior cingulate cortex, pre-supplementary motor area, ventral medial prefrontal cortex) across 41 sessions from 21 patients that underwent seizure monitoring with depth electrodes. Subjects performed a screening task (907 neurons) to identify images for which highly selective cells were present. Subjects then performed a working memory task (902 neurons), in which they were sequentially presented with 1-3 images for which highly selective cells were present and, following a maintenance period, were asked if the probe was identical to one of the maintained images. This Neurodata Without Borders formatted dataset includes spike times, extracellular spike waveforms, stimuli presented, behavior, electrode locations, and subject demographics. As validation, we replicate previous findings on the selectivity of concept cells and their persistent activity during working memory maintenance. This large dataset of rare human single-neuron recordings and behavior enables the investigation of the neural mechanisms of working memory in humans.

Exercise as Treatment for "Stress-Related" Mental Disorders.

The beneficial impact of physical activity on preventing and treating mental disorders has captured growing (research) interest. This article aims to provide a concise overview of essential evidence regarding the effectiveness and underlying mechanisms of physical activity for individuals with mental disorders clustered as "stress-related" conditions. Empirical findings (e.g., longitudinalprospective studies, interventional randomized-controlled-trials, reviews, meta-analyses) regarding the effects of physical activity in the prevention and treatment of stress-related mental disorders are summarized. Furthermore, potential mechanisms underlying these effects are discussed, and recommendations regarding the use of physical activity are outlined. The majority of studies indicate good efficacy of physical activity in prospectively lowering the risk for the incidence of subsequent stress-related mental disorders as well as in the treatment of manifest disorders. Most evidence targets unipolar depressive disorder and, secondly, anxiety disorders. Research regarding posttraumatic stress disorder, obsessive-compulsive disorders, and somatoform disorders is promising but scarce. Physical activity seems to be useful as a stand-alone-treatment as well as in combination with other psychotherapeutic or pharmacological treatments. Multiple intertwined physiological, psychological, and social mechanisms are assumed to mediate the beneficial effects. Recommendations regarding physical activity can orientate on official guidelines but should consider the individual needs and circumstances of each subject. In summary, physical activity seems to be effective in the prevention and treatment of stressrelated mental disorders and, therefore, should be fostered in healthcare-settings. Future studies are needed to clarify partly inconsistent patterns of results and to close research gaps, e.g., concerning somatoform disorders.

Resistance Training in Depression.

BACKGROUND: More than 320 million people around the world suffer from depression. Physical activity and sports are effective treatment strategies. Endurance training has already been intensively studied, but any potential antidepressant effect of resistance training is unknown at present, nor is it clear whether this could yield any relevant benefit in clinical use. METHODS: The PubMed database was selectively searched for recent studies and review articles concerning the use, efficacy, and safety of resistance training in persons with depressive symptoms and diagnosed depression. RESULTS: Two meta-analyses revealed that resistance training alleviated depressive symptoms with a low to moderate effect size (0.39-0.66). Resistance training in patients with diagnosed depression was studied in seven randomized controlled trials, in which the duration of the intervention ranged from eight weeks to eight months. In six of these trials, the depressive symptoms were reduced. In one trial, a persistent benefit was seen in the resistance-training group at 26 months of follow-up (adherence, 33%). Moreover, resistance training improved strength, quality of life, and quality of sleep. No serious adverse events occurred; this indicates that resistance training in depression is safe. CONCLUSION: Resistance training seems to have an antidepressant effect. Open questions remain concerning its effects in different age groups, as well as the optimal training parameters. Further high-quality trials will be needed to document the effect of resistance training more conclusively and to enable the formulation of treatment recommendations.

Control of working memory maintenance by theta-gamma phase amplitude coupling of human hippocampal neurons.

Retaining information in working memory (WM) is a demanding process that relies on cognitive control to protect memoranda-specific persistent activity from interference. How cognitive control regulates WM storage, however, remains unknown. We hypothesized that interactions of frontal control and hippocampal persistent activity are coordinated by theta-gamma phase amplitude coupling (TG-PAC). We recorded single neurons in the human medial temporal and frontal lobe while patients maintained multiple items in WM. In the hippocampus, TG-PAC was indicative of WM load and quality. We identified cells that selectively spiked during nonlinear interactions of theta phase and gamma amplitude. These PAC neurons were more strongly coordinated with frontal theta activity when cognitive control demand was high, and they introduced information-enhancing and behaviorally relevant noise correlations with persistently active neurons in the hippocampus. We show that TG-PAC integrates cognitive control and WM storage to improve the fidelity of WM representations and facilitate behavior.

Predicting Behavioral Threshold at 6 and 8 kHz for Children and Adults Based on the Auditory Brainstem Response.

PURPOSE: Common clinical application of auditory brainstem response (ABR) testing is limited to 0.25-4 kHz. Prior research has demonstrated associations between ABR and behavioral thresholds for tone burst stimuli > 4 kHz in adults, but there are no comparable data for children. The ability to predict behavioral thresholds > 4 kHz clinically based on the ABR would provide valuable audiologic information for individuals who are unable to provide behavioral thresholds. This study included children with hearing loss and children with normal hearing to determine the association between ABR and behavioral thresholds at 6 and 8 kHz. METHOD: ABR and behavioral thresholds were obtained for children ages 4.7-16.7 years (M = 10.5, SD = 3.4) with sensorineural hearing loss (n = 24) or normal hearing sensitivity (n = 16) and for adults ages 18.4-54.4 years (M = 32.7, SD = 10.4) with sensorineural hearing loss (n = 13) or normal hearing sensitivity (n = 11). Thresholds obtained for 6 and 8 kHz using ABR and conventional audiometry were compared. RESULTS: Differences between ABR and behavioral thresholds averaged 5-6 dB for both children and adults for both test frequencies, with differences of ≤ 20 dB in all instances. Linear mixed modeling for data from participants with hearing loss suggested that ABR threshold is a good predictor of behavioral threshold at 6 and 8 kHz for both children and adults. Test specificity was 100%; no participants with behavioral thresholds ≤ 20 dB HL had ABR thresholds > 25 dB nHL. CONCLUSIONS: Initial evidence suggests that ABR testing at 6 and 8 kHz is reliable for estimating behavioral threshold in listeners with hearing loss and accurately identifies normal hearing sensitivity. The results of this study contribute to efforts to improve outcomes for vulnerable populations by reducing barriers to clinical implementation of ABR testing at > 4 kHz.

Social buffering diminishes fear response but does not equal improved fear extinction.

Social support during exposure-based psychotherapy is believed to diminish fear and improve therapy outcomes. However, some clinical trials challenge that notion. Underlying mechanisms remain unknown, hindering the understanding of benefits and pitfalls of such approach. To study social buffering during fear extinction, we developed a behavioral model in which partner's presence decreases response to fear-associated stimuli. To identify the neuronal background of this phenomenon, we combined behavioral testing with c-Fos mapping, optogenetics, and chemogenetics. We found that the presence of a partner during fear extinction training causes robust inhibition of freezing; the effect, however, disappears in subjects tested individually on the following day. It is accompanied by lowered activation of the prelimbic (PL) and anterior cingulate (ACC) but not infralimbic (IL) cortex. Accordingly, blocking of IL activity left social buffering intact. Similarly, inhibition of the ventral hippocampus-PL pathway, suppressing fear response after prolonged extinction training, did not diminish the effect. In contrast, inhibition of the ACC-central amygdala pathway, modulating social behavior, blocked social buffering. By reporting that social modulation of fear inhibition is transient and insensitive to manipulation of the fear extinction-related circuits, we show that the mechanisms underlying social buffering during extinction are different from those of individual extinction.

Pylabianca: comprehensive and user­friendly Python package for single­neuron data analysis.

In the area of electrophysiology, the availability of comprehensive and user­friendly tools for single-neuron data processing, statistical analysis, and fast, intuitive data visualization is limited. To address this gap, we introduce pylabianca, a Python library tailored for robust single and multi­unit data processing. Pylabianca leverages the power of standard Python packages and adopts the application programming interface of MNE­Python, one of the most widely used electrophysiology packages. One of pylabianca's primary objectives is to provide a low entry threshold for scientists, requiring only basic Python programming skills. Pylabianca was designed to streamline most common analyses of single neuron data, and provide convenient data structures to serve as a foundation for building custom analysis pipelines. We believe that pylabianca will contribute to enhancing researchers' capabilities and efficiency in the field of single-neuron electrophysiology.

Auditory Brainstem Responses at 6 and 8 kHz in Infants With Normal Hearing.

PURPOSE: Normative auditory brainstem response (ABR) data for infants and young children are available for 0.25-4 kHz, limiting clinical assessment to this range. As such, the high-frequency hearing sensitivity of infants and young children remains unknown until behavioral testing can be completed, often not until late preschool or early school ages. The purpose of this study was to obtain normative ABR data at 6 and 8 kHz in young infants. METHOD: Participants were 173 full-term infants seen clinically for ABR testing at 0.4-6.7 months chronological age (M = 1.4 months, SD = 1.0), 97% of whom were ≤ 12 weeks chronological age. Stimuli included 6 and 8 kHz tone bursts presented at a rate of 27.7/s or 30.7/s using Blackman window gating with six cycles (6 kHz) or eight cycles (8 kHz) rise/fall time and no plateau. Presentation levels included 20, 40, and 60 dB nHL. The ABR threshold was estimated in 5- to 10-dB steps. RESULTS: As previously observed with lower frequency stimuli, ABR waveforms obtained in response to 6 and 8 kHz tone bursts decreased in latency with increasing intensity and increasing age. Latency was shorter for 8-kHz tone bursts than 6-kHz tone bursts. Data tables are presented for clinical reference for infants ≤ 4 weeks, 4.1-8 weeks, and 8.1-12 weeks chronological age including median ABR latency for Waves I, III, and V and the upper and lower boundaries of the 90% prediction interval. Interpeak Latencies I-III, III-V, and I-V are also reported. CONCLUSION: The results from this study demonstrate that ABR assessment at 6 and 8 kHz is feasible for young infants within a standard clinical appointment and provide reference data for clinical interpretation of ABR waveforms for frequencies above 4 kHz.

[Sports psychiatry and psychotherapy]. / Sportpsychiatrie und -psychotherapie.

Sports psychiatry and psychotherapy is a relatively young field and is comprised of two key segments: the special features of the diagnostics and therapy of mental disorders in elite athletes and the use of exercise and sports in the development and treatment of mental disorders. Although all mental disorders can in principle also occur in (elite) athletes, there are additionally sport-specific mental disorders, such as anorexia athletica and other eating disorders, chronic traumatic encephalopathy, misuse of and dependency on performance-enhancing substances (doping) and muscle dysmorphia. Many high-quality clinical trials over the past two decades have been able to demonstrate a therapeutic efficacy of physical activity and sport in the treatment of various mental disorders. All clinicians active in psychiatry and psychotherapy should possess a basic knowledge of sports psychiatry.

Cognitive neuroscience: Theta network oscillations coordinate development of episodic memory.

Our ability to remember life events matures through childhood and adolescence. A new study has revealed how theta oscillations between two anatomical brain regions supporting memory and executive functions are synchronized and develop across age through functional and structural connectivity.

How Human Single-Neuron Recordings Can Help Us Understand Cognition: Insights from Memory Studies.

Understanding human cognition is a key goal of contemporary neuroscience. Due to the complexity of the human brain, animal studies and noninvasive techniques, however valuable, are incapable of providing us with a full understanding of human cognition. In the light of existing cognitive theories, we describe findings obtained thanks to human single-neuron recordings, including the discovery of concept cells and novelty-dependent cells, or activity patterns behind working memory, such as persistent activity. We propose future directions for studies using human single-neuron recordings and we discuss possible opportunities of investigating pathological brain.

Cellular Classes in the Human Brain Revealed In Vivo by Heartbeat-Related Modulation of the Extracellular Action Potential Waveform.

Determining cell types is critical for understanding neural circuits but remains elusive in the living human brain. Current approaches discriminate units into putative cell classes using features of the extracellular action potential (EAP); in absence of ground truth data, this remains a problematic procedure. We find that EAPs in deep structures of the brain exhibit robust and systematic variability during the cardiac cycle. These cardiac-related features refine neural classification. We use these features to link bio-realistic models generated from in vitro human whole-cell recordings of morphologically classified neurons to in vivo recordings. We differentiate aspiny inhibitory and spiny excitatory human hippocampal neurons and, in a second stage, demonstrate that cardiac-motion features reveal two types of spiny neurons with distinct intrinsic electrophysiological properties and phase-locking characteristics to endogenous oscillations. This multi-modal approach markedly improves cell classification in humans, offers interpretable cell classes, and is applicable to other brain areas and species.

Combined Phase-Rate Coding by Persistently Active Neurons as a Mechanism for Maintaining Multiple Items in Working Memory in Humans.

Maintaining multiple items in working memory (WM) is central to human behavior. Persistently active neurons are thought to be a mechanism to maintain WMs, but it remains unclear how such activity is coordinated when multiple items are kept in memory. We show that memoranda-selective persistently active neurons in the human medial temporal lobe phase lock to ongoing slow-frequency (1-7 Hz) oscillations during WM maintenance. The properties of phase locking are dependent on memory content and load. During high memory loads, the phase of the oscillatory activity to which neurons phase lock provides information about memory content not available in the firing rate of the neurons. We provide a computational model that reveals that inhibitory-feedback-mediated competition between multiple persistently active neurons reproduces this phenomenon. This work reveals a mechanism for the active maintenance of multiple items in WM that relies on persistently active neurons whose activation is orchestrated by oscillatory activity.

Between persistently active and activity-silent frameworks: novel vistas on the cellular basis of working memory.

Recent work has revealed important new discoveries on the cellular mechanisms of working memory (WM). These findings have motivated several seemingly conflicting theories on the mechanisms of short-term memory maintenance. Here, we summarize the key insights gained from these new experiments and critically evaluate them in light of three hypotheses: classical persistent activity, activity-silent, and dynamic coding. The experiments discussed include the first direct demonstration of persistently active neurons in the human medial temporal lobe that form static attractors with relevance to WM, single-neuron recordings in the macaque prefrontal cortex that show evidence for both persistent and more dynamic types of WM representations, and noninvasive neuroimaging in humans that argues for activity-silent representations. A key insight that emerges from these new results is that there are several neural mechanisms that support the maintenance of information in WM. Finally, based on established cognitive theories of WM, we propose a coherent model that encompasses these seemingly contradictory results. We propose that the three neuronal mechanisms of persistent activity, activity-silent, and dynamic coding map well onto the cognitive levels of information processing (within focus of attention, activated long-term memory, and central executive) that Cowan's WM model proposes.