Lesion network guided delta frequency neuromodulation improves cognition in patients with psychosis spectrum disorders: A pilot study.

BACKGROUND: Transcranial electric stimulation (tES) may improve cognition in psychosis spectrum disorders. However, few studies have used novel tES approaches, such as high definition tES (HD-tES) to target specific brain circuits. Recently, the extrastriate visual cortex (V5/MT) has been causally linked to visual hallucinations through lesion network mapping and this may be a promising approach for improving cognition. OBJECTIVE: We aim to determine if causal lesion network guided HD-tES to V5/MT improves cognitive performance as measured by the Brief Assessment of Cognition in Schizophrenia (BACS). METHODS: A single-blind pilot study with a within-subjects crossover design was performed to characterize the effect of cathodal HD-transcranial direct current stimulation (tDCS) and 2 Hz HD-transcranial alternating current stimulation (tACS) on cognition. Enrolled patients received 20 mins of HD-tES twice daily for 5 consecutive days applied bilaterally to V5/MT with a washout between conditions. BACS assessments were performed at baseline, day-5, and 1-month. RESULTS: 6 participants with psychosis spectrum disorder were enrolled. 6 individuals received cathodal HD-tDCS. 4 individuals received 2 Hz HD-tACS. HD-tACS resulted in significant (p < 0.1 baseline to 1-month improvements for Digit Sequencing, Verbal Fluency, and Tower of London. HD-tDCS did not result in significant improvement on any task. CONCLUSIONS: HD-tACS targeting V5/MT may be a promising treatment to improve cognitive abilities in individuals with psychosis. By promoting delta oscillations, tACS may enhance cortico-cortico communications across brain networks to improve verbal working memory, processing speed, and executive function. Large-scale investigations are needed to replicate these results.

Toxoplasma gondii, a plea for a thorough investigation of its oncogenic potential.

It is estimated that 30 % of the world's population harbours the parasite Toxoplasma gondii, particularly in the brain. Beyond its implication in potentially severe opportunistic or congenital infections, this persistence has long been considered as without consequence. However, certain data in animals and humans suggest that this carriage may be linked to various neuropsychiatric or neurodegenerative disorders. The hypothesis of a potential cerebral oncogenicity of the parasite is also emerging. In this personal view, we will present the epidemiological arguments in favour of an association between toxoplasmosis and cerebral malignancy, before considering the points that could underlie a potential causal link. More specifically, we will focus on the brain as the preferred location for T. gondii persistence and the propensity of this parasite to interfere with the apoptosis and cell cycle signalling pathways of their host cell.

A pilot study to investigate the efficacy and tolerability of lesion network guided transcranial electrical stimulation in outpatients with psychosis spectrum illness.

BACKGROUND: Transcranial electrical stimulation (tES) may improve psychosis symptoms, but few investigations have targeted brain regions causally linked to psychosis symptoms. We implemented a novel montage targeting the extrastriate visual cortex (eVC) previously identified by lesion network mapping in the manifestation of visual hallucinations. OBJECTIVE: To determine if lesion network guided High Definition-tES (HD-tES) to the eVC is safe and efficacious in reducing symptoms related to psychosis. METHODS: We conducted a single-blind crossover pilot study (NCT04870710) in patients with psychosis spectrum disorders. Participants first received HD-tDCS (direct current), followed by 4 weeks of wash out, then 2 Hz HD-tACS (alternating current). Participants received 5 days of daily (2×20 min) stimulation bilaterally to the eVC. Primary outcomes included the Positive and Negative Syndrome Scale (PANSS), biological motion task, and Event Related Potentials (ERP) from a steady state visual evoked potential (SSVEP) paradigm. Secondary outcomes included the Montgomery-Asperg Depression Rating Scale, Global Assessment of Functioning (GAF), velocity discrimination and visual working memory task, and emotional ERP. RESULTS: HD-tDCS improved PANSS general psychopathology in the short-term (d=0.47; pfdr=0.03), with long-term improvements in general psychopathology (d=0.62; pfdr=0.05) and GAF (d=-0.56; pfdr=0.04) with HD-tACS. HD-tDCS reduced SSVEP P1 (d=0.25; pfdr=0.005), which correlated with general psychopathology (ß = 0.274, t = 3.59, p = 0.04). No significant differences in safety or tolerability measures were identified. CONCLUSION: Lesion network guided HD-tES to the eVC is a safe, efficacious, and promising approach for reducing general psychopathology via changes in neuroplasticity. These results highlight the need for larger clinical trials implementing novel targeting methodologies for the treatments of psychosis.

A new ape from Türkiye and the radiation of late Miocene hominines.

Fossil apes from the eastern Mediterranean are central to the debate on African ape and human (hominine) origins. Current research places them either as hominines, as hominins (humans and our fossil relatives) or as stem hominids, no more closely related to hominines than to pongines (orangutans and their fossil relatives). Here we show, based on our analysis of a newly identified genus, Anadoluvius, from the 8.7 Ma site of Çorakyerler in central Anatolia, that Mediterranean fossil apes are diverse, and are part of the first known radiation of early members of the hominines. The members of this radiation are currently only identified in Europe and Anatolia; generally accepted hominins are only found in Africa from the late Miocene until the Pleistocene. Hominines may have originated in Eurasia during the late Miocene, or they may have dispersed into Eurasia from an unknown African ancestor. The diversity of hominines in Eurasia suggests an in situ origin but does not exclude a dispersal hypothesis.

A meta-analysis suggests that tACS improves cognition in healthy, aging, and psychiatric populations.

Transcranial alternating current stimulation (tACS) has attracted interest as a technique for causal investigations into how rhythmic fluctuations in brain neural activity influence cognition and for promoting cognitive rehabilitation. We conducted a systematic review and meta-analysis of the effects of tACS on cognitive function across 102 published studies, which included 2893 individuals in healthy, aging, and neuropsychiatric populations. A total of 304 effects were extracted from these 102 studies. We found modest to moderate improvements in cognitive function with tACS treatment that were evident in several cognitive domains, including working memory, long-term memory, attention, executive control, and fluid intelligence. Improvements in cognitive function were generally stronger after completion of tACS ("offline" effects) than during tACS treatment ("online" effects). Improvements in cognitive function were greater in studies that used current flow models to optimize or confirm neuromodulation targets by stimulating electric fields generated in the brain by tACS protocols. In studies targeting multiple brain regions concurrently, cognitive function changed bidirectionally (improved or decreased) according to the relative phase, or alignment, of the alternating current in the two brain regions (in phase versus antiphase). We also noted improvements in cognitive function separately in older adults and in individuals with neuropsychiatric illnesses. Overall, our findings contribute to the debate surrounding the effectiveness of tACS for cognitive rehabilitation, quantitatively demonstrate its potential, and indicate further directions for optimal tACS clinical study design.

Efficacy and Tolerability of Lesion Network Guided Transcranial Electrical Stimulation in Outpatients with Psychosis Spectrum Illness: A Nonrandomized Controlled Trial.

Importance: Transcranial electrical stimulation (tES) may improve psychosis symptoms, but few investigations have targeted brain regions causally linked to psychosis symptoms. We implemented a novel montage targeting the extrastriate visual cortex (eVC) previously identified by lesion network mapping in the manifestation of visual hallucinations. Objective: To determine if lesion network guided HD-tES to the eVC is safe and efficacious in reducing symptoms related to psychosis. Design Setting and Participants: Single-center, nonrandomized, single-blind trial using a crossover design conducted in two 4-week phases beginning November 2020, and ending January 2022. Participants were adults 18-55 years of age with a diagnosis of schizophrenia, schizoaffective or psychotic bipolar disorder as confirmed by the Structured Clinical Interview for DSM-V, without an antipsychotic medication change for at least 4 weeks. A total of 8 participants consented and 6 participants enrolled. Significance threshold set to <0.1 due to small sample size. Interventions: 6 Participants first received HD-tDCS (direct current), followed by 4 weeks of wash out, then 4 received 2Hz HD-tACS (alternating current). Participants received 5 consecutive days of daily (2 × 20min) stimulation applied bilaterally to the eVC. Main Outcomes and Measures: Primary outcomes included the Positive and Negative Syndrome Scale (PANSS) total, positive, negative, and general scores, biological motion task, and Event Related Potential (ERP) measures obtained from a steady state visual evoked potential (SSVEP) task across each 4-week phase. Secondary outcomes included the Montgomery-Asperg Depression Rating Scale (MADRS), Global Assessment of Functioning (GAF), velocity discrimination task, visual working memory task, and emotional ERP across each 4-week phase. Results: HD-tDCS improved general psychopathology in the short-term (d=0.47; p fdr =0.03), with long-term improvements in general psychopathology (d=0.62; p fdr =0.05) and GAF (d=-0.56; p fdr =0.04) with HD-tACS. HD-tDCS reduced SSVEP P1 (d=0.25; p fdr =0.005), which correlated with general psychopathology (ß=0.274, t=3.59, p=0.04). No significant differences in safety or tolerability measures were identified. Conclusions and Relevance: Lesion network guided HD-tES to the eVC is a safe, efficacious, and promising approach for reducing general psychopathology via changes in neuroplasticity. These results highlight the need for larger clinical trials implementing novel targeting methodologies for the treatments of psychosis. Trial Registration: ClinicalTrials.gov Identifier: NCT04870710. Key Points: Question: Is lesion network guided neurostimulation an efficacious, safe, and targeted approach for treating psychosis?Findings: In this single-center, nonrandomized, crossover, single-blind trial of 6 outpatients with psychosis, improvement in general psychopathology was seen in the short-term with HD-tDCS (high-definition transcranial direct current stimulation) and long-term with HD-tACS (alternating current) targeting the extrastriate visual cortex (eVC). HD-tDCS reduced early visual evoked responses which linked to general psychopathology improvements. Overall, both stimulations were well tolerated.Meaning: Study findings suggest that lesion network guided HD-tES to the eVC is a safe, efficacious, and promising approach for reducing general psychopathology via neuroplastic changes.

Dissociable rhythmic mechanisms enhance memory for conscious and nonconscious perceptual contents.

Understanding the neural mechanisms of conscious and unconscious experience is a major goal of fundamental and translational neuroscience. Here, we target the early visual cortex with a protocol of noninvasive, high-resolution alternating current stimulation while participants performed a delayed target-probe discrimination task and reveal dissociable mechanisms of mnemonic processing for conscious and unconscious perceptual contents. Entraining ß-rhythms in bilateral visual areas preferentially enhanced short-term memory for seen information, whereas α-entrainment in the same region preferentially enhanced short-term memory for unseen information. The short-term memory improvements were frequency-specific and long-lasting. The results add a mechanistic foundation to existing theories of consciousness, call for revisions to these theories, and contribute to the development of nonpharmacological therapeutics for improving visual cortical processing.

Synchronizing neural rhythms.

Personalized, noninvasive network-based neuromodulation aids impaired cognition.

Long-lasting, dissociable improvements in working memory and long-term memory in older adults with repetitive neuromodulation.

The development of technologies to protect or enhance memory in older people is an enduring goal of translational medicine. Here we describe repetitive (4-day) transcranial alternating current stimulation (tACS) protocols for the selective, sustainable enhancement of auditory-verbal working memory and long-term memory in 65-88-year-old people. Modulation of synchronous low-frequency, but not high-frequency, activity in parietal cortex preferentially improved working memory on day 3 and day 4 and 1 month after intervention, whereas modulation of synchronous high-frequency, but not low-frequency, activity in prefrontal cortex preferentially improved long-term memory on days 2-4 and 1 month after intervention. The rate of memory improvements over 4 days predicted the size of memory benefits 1 month later. Individuals with lower baseline cognitive function experienced larger, more enduring memory improvements. Our findings demonstrate that the plasticity of the aging brain can be selectively and sustainably exploited using repetitive and highly focalized neuromodulation grounded in spatiospectral parameters of memory-specific cortical circuitry.

An Integrated Neuroimaging Approach to Inform Transcranial Electrical Stimulation Targeting in Visual Hallucinations.

ABSTRACT: For decades, noninvasive brain stimulation (NIBS), such as transcranial electrical stimulation (tES), has been used to directly modulate human brain mechanisms of visual perception, setting the groundwork for the development of novel circuit-based therapies. While the field of NIBS has grown considerably over recent years, few studies have used these technologies to treat visual hallucinations (VH). Here, we review the NIBS-VH literature and find mixed results due to shortcomings that may potentially be addressed with a unique multimodal neuroimaging-NIBS approach. We highlight methodological advances in NIBS research that have provided researchers with more precise anatomical measurements that may improve our ability to influence brain activity. Specifically, we propose a methodology that combines neuroimaging advances, clinical neuroscience developments such as the identification of brain regions causally involved in VH, and personalized NIBS approaches that improve anatomical targeting. This methodology may enable us to reconcile existing discrepancies in tES-VH research and pave the way for more effective, VH-specific protocols for treating a number of neuropsychiatric disorders with VH as a core symptom.

Alpha suppression indexes a spotlight of visual-spatial attention that can shine on both perceptual and memory representations.

Although researchers have been recording the human electroencephalogram (EEG) for almost a century, we still do not completely understand what cognitive processes are measured by the activity of different frequency bands. The 8- to 12-Hz activity in the alpha band has long been a focus of this research, but our understanding of its links to cognitive mechanisms has been rapidly evolving recently. Here, we review and discuss the existing evidence for two competing perspectives about alpha activity. One view proposes that the suppression of alpha-band power following the onset of a stimulus array measures attentional selection. The competing view is that this same activity measures the buffering of the task-relevant representations in working memory. We conclude that alpha-band activity following the presentation of stimuli appears to be due to the operation of an attentional selection mechanism, with characteristics that mirror the classic views of attention as selecting both perceptual inputs and representations already stored in memory.

High-frequency neuromodulation improves obsessive-compulsive behavior.

Nearly one billion people worldwide suffer from obsessive-compulsive behaviors1,2, yet our mechanistic understanding of these behaviors is incomplete, and effective therapeutics are unavailable. An emerging perspective characterizes obsessive-compulsive behaviors as maladaptive habit learning3,4, which may be associated with abnormal beta-gamma neurophysiology of the orbitofrontal-striatal circuitry during reward processing5,6. We target the orbitofrontal cortex with alternating current, personalized to the intrinsic beta-gamma frequency of the reward network, and show rapid, reversible, frequency-specific modulation of reward- but not punishment-guided choice behavior and learning, driven by increased exploration in the setting of an actor-critic architecture. Next, we demonstrate that chronic application of the procedure over 5 days robustly attenuates obsessive-compulsive behavior in a non-clinical population for 3 months, with the largest benefits for individuals with more severe symptoms. Finally, we show that convergent mechanisms underlie modulation of reward learning and reduction of obsessive-compulsive symptoms. The results contribute to neurophysiological theories of reward, learning and obsessive-compulsive behavior, suggest a unifying functional role of rhythms in the beta-gamma range, and set the groundwork for the development of personalized circuit-based therapeutics for related disorders.

Synchronizing Brain Rhythms to Improve Cognition.

Impaired cognition is common in many neuropsychiatric disorders and severely compromises quality of life. Synchronous electrophysiological rhythms represent a core mechanism for sculpting communication dynamics among large-scale brain networks that underpin cognition and its breakdown in neuropsychiatric disorders. Here, we review an emerging neuromodulation technology called transcranial alternating current stimulation that has shown remarkable early results in rapidly improving various domains of human cognition by modulating properties of rhythmic network synchronization. Future noninvasive neuromodulation research holds promise for potentially rescuing network activity patterns and improving cognition, setting groundwork for the development of drug-free, circuit-based therapeutics for people with cognitive brain disorders.

Working memory revived in older adults by synchronizing rhythmic brain circuits.

Understanding normal brain aging and developing methods to maintain or improve cognition in older adults are major goals of fundamental and translational neuroscience. Here we show a core feature of cognitive decline-working-memory deficits-emerges from disconnected local and long-range circuits instantiated by theta-gamma phase-amplitude coupling in temporal cortex and theta phase synchronization across frontotemporal cortex. We developed a noninvasive stimulation procedure for modulating long-range theta interactions in adults aged 60-76 years. After 25 min of stimulation, frequency-tuned to individual brain network dynamics, we observed a preferential increase in neural synchronization patterns and the return of sender-receiver relationships of information flow within and between frontotemporal regions. The end result was rapid improvement in working-memory performance that outlasted a 50 min post-stimulation period. The results provide insight into the physiological foundations of age-related cognitive impairment and contribute to groundwork for future non-pharmacological interventions targeting aspects of cognitive decline.

Localization and Elimination of Attentional Dysfunction in Schizophrenia During Visual Search.

Theories of the locus of visual selective attention dysfunction in schizophrenia propose that the deficits arise from either an inability to maintain working memory representations that guide attention, or difficulty focusing lower-level visual attention mechanisms. However, these theoretical accounts neglect the role of long-term memory representations in controlling attention. Here, we show that the control of visual attention is impaired in people with schizophrenia, and that this impairment is driven by an inability to shift top-down attentional control from working memory to long-term memory across practice. Next, we provide converging evidence for the source of attentional impairments in long-term memory by showing that noninvasive electrical stimulation of medial frontal cortex normalizes long-term memory related neural signatures and patients' behavior. Our findings suggest that long-term memory structures may be a source of impaired attentional selection in schizophrenia when visual attention is taxed during the processing of multi-object arrays.