Treatment Of Brain Disorders Research Articles

Designing and validating a robust adaptive neuromodulation algorithm for closed-loop control of brain states

Objective. Neuromodulation systems that use closed-loop brain stimulation to control brain states can provide new therapies for brain disorders. To date, closed-loop brain stimulation has largely used linear time-invariant controllers. However, nonlinear time-varying brain network dynamics and external disturbances can appear during real-time stimulation, collectively leading to real-time model uncertainty. Real-time model uncertainty can degrade the performance or even cause instability of time-invariant controllers. Three problems need to be resolved to enable accurate and stable control under model uncertainty. First, an adaptive controller is needed to track the model uncertainty. Second, the adaptive controller additionally needs to be robust to noise and disturbances. Third, theoretical analyses of stability and robustness are needed as prerequisites for stable operation of the controller in practical applications. Approach. We develop a robust adaptive neuromodulation algorithm that solves the above three problems. First, we develop a state-space brain network model that explicitly includes nonlinear terms of real-time model uncertainty and design an adaptive controller to track and cancel the model uncertainty. Second, to improve the robustness of the adaptive controller, we design two linear filters to increase steady-state control accuracy and reduce sensitivity to high-frequency noise and disturbances. Third, we conduct theoretical analyses to prove the stability of the neuromodulation algorithm and establish a trade-off between stability and robustness, which we further use to optimize the algorithm design. Finally, we validate the algorithm using comprehensive Monte Carlo simulations that span a broad range of model nonlinearity, uncertainty, and complexity. Main results. The robust adaptive neuromodulation algorithm accurately tracks various types of target brain state trajectories, enables stable and robust control, and significantly outperforms state-of-the-art neuromodulation algorithms. Significance. Our algorithm has implications for future designs of precise, stable, and robust closed-loop brain stimulation systems to treat brain disorders and facilitate brain functions.

Stimulation Montage Achieves Balanced Focality and Intensity

Transcranial direct current stimulation (tDCS) is a non-invasive neuromodulation technique to treat brain disorders by using a constant, low current to stimulate targeted cortex regions. Compared to the conventional tDCS that uses two large pad electrodes, multiple electrode tDCS has recently received more attention. It is able to achieve better stimulation performance in terms of stimulation intensity and focality. In this paper, we first establish a computational model of tDCS, and then propose a novel optimization algorithm using a regularization matrix λ to explore the balance between stimulation intensity and focality. The simulation study is designed such that the performance of state-of-the-art algorithms and the proposed algorithm can be compared via quantitative evaluation. The results show that the proposed algorithm not only achieves desired intensity, but also smaller target error and better focality. Robustness analysis indicates that the results are stable within the ranges of scalp and cerebrospinal fluid (CSF) conductivities, while the skull conductivity is most sensitive and should be carefully considered in real clinical applications.

Exploring CNS Effects of American Traditional Medicines using Zebrafish Models.

Although American traditional medicine (ATM) has been practiced for millennia, its complex multi-target mechanisms of therapeutic action remain poorly understood. Animal models are widely used to elucidate the therapeutic effects of various ATMs, including their modulation of brain and behavior. Complementing rodent models, the zebrafish (Danio rerio) is a promising novel organism in translational neuroscience and neuropharmacology research. Here, we emphasize the growing value of zebrafish for testing neurotropic effects of ATMs and outline future directions of research in this field. We also demonstrate the developing utility of zebrafish as complementary models for probing CNS mechanisms of ATM action and their potential to treat brain disorders.

Recent Trend of Ultrasound-Mediated Nanoparticle Delivery for Brain Imaging and Treatment.

In view of the fact that the blood-brain barrier (BBB) prevents the transport of imaging probes and therapeutic agents to the brain and thus hinders the diagnosis and treatment of brain-related disorders, methods of circumventing this problem (e.g., ultrasound-mediated nanoparticle delivery) have drawn much attention. Among the related techniques, focused ultrasound (FUS) is a favorite means of enhancing drug delivery via transient BBB opening. Photoacoustic brain imaging relies on the conversion of light into heat and the detection of ultrasound signals from contrast agents, offering the benefits of high resolution and large penetration depth. The extensive versatility and adjustable physicochemical properties of nanoparticles make them promising therapeutic agents and imaging probes, allowing for successful brain imaging and treatment through the combined action of ultrasound and nanoparticulate agents. FUS-induced BBB opening enables nanoparticle-based drug delivery systems to efficiently access the brain. Moreover, photoacoustic brain imaging using nanoparticle-based contrast agents effectively visualizes brain morphologies or diseases. Herein, we review the progress in the simultaneous use of nanoparticles and ultrasound in brain research, revealing the potential of ultrasound-mediated nanoparticle delivery for the effective diagnosis and treatment of brain disorders.

Regulation of AMPAR trafficking in synaptic plasticity by BDNF and the impact of neurodegenerative disease.

Research demonstrates that the neural mechanisms underlying synaptic plasticity and learning and memory involve mobilization of AMPA-type neurotransmitter receptors at glutamatergic synaptic contacts, and that these mechanisms are targeted during neurodegenerative disease. Strengthening neural transmission occurs with insertion of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) into synapses while weakening results from receptor withdrawal. A key player in the trafficking of AMPARs during plasticity and learning is the brain-derived neurotrophic factor (BDNF) signaling system. BDNF is a neurotrophic factor that supports neuronal growth and is required for learning and memory. Significantly, a primary feature of many neurodegenerative diseases is a reduction in BDNF protein as well as disrupted neuronal surface expression of synaptic AMPARs. The resulting weakening of synaptic contacts leads to synapse loss and neuronal degeneration that underlies the cognitive impairment and dementia observed in patients with progressive neurodegenerative disease such as Alzheimer's. In the face of these data, one therapeutic approach is to increase BDNF bioavailability in brain. While this has been met with significant challenges, the results of the research have been promising. In spite of this, there are currently no clinical trials to test many of these findings on patients. Here, research showing that BDNF drives AMPARs to synapses, AMPAR trafficking is essential for synaptic plasticity and learning, and that neurodegenerative disease results in a significant decline in BDNF will be reviewed. The aim is to draw attention to the need for increasing patient-directed clinical studies to test the possible benefits of increasing levels of neurotrophins, specifically BDNF, to treat brain disorders. Much is known about the cellular mechanisms that underlie learning and memory in brain. It can be concluded that signaling by neurotrophins like BDNF and AMPA-type glutamate receptor synaptic trafficking are fundamental to these processes. Data from animal models and patients reveal that these mechanisms are adversely targeted during neurodegenerative disease and results in memory loss and cognitive decline. A brief summary of our understanding of these mechanisms indicates that it is time to apply this knowledge base directly to development of therapeutic treatments that enhance neurotrophins for brain disorders in patient populations.

EEG signatures change during unilateral Yogi nasal breathing

Airflow through the left-and-right nostrils is said to be entrained by an endogenous nasal cycle paced by both poles of the hypothalamus. Yogic practices suggest, and scientific evidence demonstrates, that right-nostril breathing is involved with relatively higher sympathetic activity (arousal states), while left-nostril breathing is associated with a relatively more parasympathetic activity (stress alleviating state). The objective of this study was to further explore this laterality by controlling nasal airflow and observing patterns of cortical activity through encephalographic (EEG) recordings. Thirty subjects participated in this crossover study. The experimental session consisted of a resting phase (baseline), then a period of unilateral nostril breathing (UNB) using the dominant nasal airway, followed by UNB using the non-dominant nasal airway. A 64-channel EEG was recorded throughout the whole session. The effects of nostril-dominance, and nostril-lateralization were assessed using the power spectral density of the neural activity. The differences in power-spectra and source localization were calculated between EEG recorded during UNB and baseline for delta, theta, alpha, beta and gamma bands. Cluster-based permutation tests showed that compared to baseline, EEG spectral power was significantly (1) decreased in all frequency bands for non-dominant nostril UNB, (2) decreased in alpha, beta and gamma bands for dominant nostril UNB, (3) decreased in all bands for left nostril UNB, and (4) decreased in all bands except delta for right nostril UNB. The beta band showed the most widely distributed changes across the scalp. our source localisation results show that breathing with the dominant nostril breathing increases EEG power in the left inferior frontal (alpha band) and left parietal lobule (beta band), whereas non-dominant nostril breathing is related to more diffuse and bilateral effects in posterior areas of the brain.These preliminary findings may stimulate further research in the area, with potential applications to tailored treatment of brain disorders associated with disruption of sympathetic and parasympathetic activity.

Effect of Ustukhuddus Alavi, a multi-herbal product, on the cognitive performance of adolescent female students

Ethnopharmacological relevanceUstukhuddus Alavi is a polyherbal formula which is introduced by Persian medicine scholars. It is traditionally used to treat brain disorders and is claimed to do so by preprocessing and cleansing the waste products from the brain. According to Persian medicine, the disposal of brain waste products is necessary for optimal cognitive performance. Aim of the studySustaining optimal cognitive performance is crucial for ideal quality of life and higher academic achievements in high school students. The objective of this study was to determine the effects of this multi-component herbal product on the cognitive performance and salivary cortisol levels of adolescent female students. Materials and methodsThe effect of a 6-week randomly assigned Ustukhuddus Alavi versus placebo administration on cognitive performance was assessed by the paced auditory serial addition test (PASAT) at the baseline and after the 3- and 6-week intake of Ustukhuddus Alavi or placebo and the one-month follow-up in 86 healthy female high school students in grades 10 and 11. Additionally, we measured the levels of salivary cortisol of the students pre- and post-intervention. ResultsSignificant mean difference between the Ustukhuddus Alavi and placebo groups in three of the paced auditory serial addition test (PASAT) subscales, namely mental health (p-value = 0.006), sustained attention (p-value = 0.001) and mental fatigue (p-value = 0.001), were observed after six weeks. We also found a significant difference between the mean salivary cortisol level of the two groups after the intervention (p-value = 0.047). ConclusionsThese findings reveal that the intake of the multi-ingredient herbal product Ustukhuddus Alavi for six weeks can be helpful for cognitive function and cortisol levels in female high school students. These positive effects seem to be related to the increase in sustained attention and the decrease in mental fatigue.

Potential Drug Delivery Pathways for Treatment of Alzheimer’s Disease

Alzheimer’s Disease (AD) has been one of the most prevalent neurodegenerative disorders that majorly affect patients older than 65 years old. The treatment of the disease costs over 1% of the global GDP [1], yet not many new drugs have been developed which can effectively treat AD based on its pathological characteristics. The major challenge in treating brain disorders such as AD is the Blood-Brain Barrier (BBB) which refrains most of the drug molecules from entering the brain. Through reviewing multiple papers from PubMed Central®(PMC), which is an archive of biomedical and life sciences journal literature at the U.S. National Institutes of Health’s National Library of Medicine (NIH/NLM), three promising drug delivery pathways have been investigated regarding their capabilities and effectivenesses of transporting drug molecules into the brain, which are inorganic nanoparticles, multifunctional liposomes, and transdermal delivery system. In this paper, brief introductions regarding each delivery pathway were offered, and specific experiment that supported the delivery method was presented. The advantages, as well as drawbacks of each type of delivery pathway, were also discussed in this paper.

Can we promote neural regeneration through microbiota-targeted strategies? Introducing the new concept of neurobiotics.

Can we promote neural regeneration through microbiota-targeted strategies? Introducing the new concept of neurobiotics.

Nose to Brain Drug Delivery System

The treatment of brain disorders is particularly challenging due to the presence of a variety of formidable obstacles to deliver drugs selectively and effectively to the brain. Blood-brain-barrier (BBB) constitutes the major obstacle to the uptake of drugs into the brain following systemic administration. An intranasal delivery provides some drugs with short channels to bypass the blood-brain barrier (BBB), especially for those with fairly low brain concentrations after a routine delivery, thus greatly enhancing the therapeutic effect on brain diseases. The nasal mucosa is nearby the brain, cerebrospinal fluid (CSF) and the drug concentrations can exceed plasma concentrations. a longer retention time at the nasal mucosal surface, penetration enhancement of the active through the nasal epithelia, and a reduction in drug metabolism in the nasal cavity. Indications where nose-to-brain products are likely to emerge first include the following: neurodegeneration, post-traumatic stress disorder, pain, and glioblastoma.

Nanotechnology Enables Novel Modalities for Neuromodulation.

Neuromodulation is of great importance both as a fundamental neuroscience research tool for analyzing and understanding the brain function, and as a therapeutic avenue for treating brain disorders. Here, an overview of conceptual and technical progress in developing neuromodulation strategies is provided, and it is suggested that recent advances in nanotechnology are enabling novel neuromodulation modalities with less invasiveness, improved biointerfaces, deeper penetration, and higher spatiotemporal precision. The use of nanotechnology and the employment of versatile nanomaterials and nanoscale devices with tailored physical properties have led to considerable research progress. To conclude, an outlook discussing current challenges and future directions for next-generation neuromodulation modalities is presented.

Gene Therapy Approach with an Emphasis on Growth Factors: Theoretical and Clinical Outcomes in Neurodegenerative Diseases.

The etiology of many neurological diseases affecting the central nervous system (CNS) is unknown and still needs more effective and specific therapeutic approaches. Gene therapy has a promising future in treating neurodegenerative disorders by correcting the genetic defects or by therapeutic protein delivery and is now an attraction for neurologists to treat brain disorders, like Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, spinal muscular atrophy, spinocerebellar ataxia, epilepsy, Huntington’s disease, stroke, and spinal cord injury. Gene therapy allows the transgene induction, with a unique expression in cells’ substrate. This article mainly focuses on the delivering modes of genetic materials in the CNS, which includes viral and non-viral vectors and their application in gene therapy. Despite the many clinical trials conducted so far, data have shown disappointing outcomes. The efforts done to improve outcomes, efficacy, and safety in the identification of targets in various neurological disorders are also discussed here. Adapting gene therapy as a new therapeutic approach for treating neurological disorders seems to be promising, with early detection and delivery of therapy before the neuron is lost, helping a lot the development of new therapeutic options to translate to the clinic.

Psychedelics and Other Psychoplastogens for Treating Mental Illness.

Psychedelics have inspired new hope for treating brain disorders, as they seem to be unlike any treatments currently available. Not only do they produce sustained therapeutic effects following a single administration, they also appear to have broad therapeutic potential, demonstrating efficacy for treating depression, post-traumatic stress disorder (PTSD), anxiety disorders, substance abuse disorder, and alcohol use disorder, among others. Psychedelics belong to a more general class of compounds known as psychoplastogens, which robustly promote structural and functional neural plasticity in key circuits relevant to brain health. Here we discuss the importance of structural plasticity in the treatment of neuropsychiatric diseases, as well as the evidence demonstrating that psychedelics are among the most effective chemical modulators of neural plasticity studied to date. Furthermore, we provide a theoretical framework with the potential to explain why psychedelic compounds produce long-lasting therapeutic effects across a wide range of brain disorders. Despite their promise as broadly efficacious neurotherapeutics, there are several issues associated with psychedelic-based medicines that drastically limit their clinical scalability. We discuss these challenges and how they might be overcome through the development of non-hallucinogenic psychoplastogens. The clinical use of psychedelics and other psychoplastogenic compounds marks a paradigm shift in neuropsychiatry toward therapeutic approaches relying on the selective modulation of neural circuits with small molecule drugs. Psychoplastogen research brings us one step closer to actually curing mental illness by rectifying the underlying pathophysiology of disorders like depression, moving beyond simply treating disease symptoms. However, determining how to most effectively deploy psychoplastogenic medicines at scale will be an important consideration as the field moves forward.

Long-Lasting Desynchronization Effects of Coordinated Reset Stimulation Improved by Random Jitters.

Abnormally strong synchronized activity is related to several neurological disorders, including essential tremor, epilepsy, and Parkinson's disease. Chronic high-frequency deep brain stimulation (HF DBS) is an established treatment for advanced Parkinson's disease. To reduce the delivered integral electrical current, novel theory-based stimulation techniques such as coordinated reset (CR) stimulation directly counteract the abnormal synchronous firing by delivering phase-shifted stimuli through multiple stimulation sites. In computational studies in neuronal networks with spike-timing-dependent plasticity (STDP), it was shown that CR stimulation down-regulates synaptic weights and drives the network into an attractor of a stable desynchronized state. This led to desynchronization effects that outlasted the stimulation. Corresponding long-lasting therapeutic effects were observed in preclinical and clinical studies. Computational studies suggest that long-lasting effects of CR stimulation depend on the adjustment of the stimulation frequency to the dominant synchronous rhythm. This may limit clinical applicability as different pathological rhythms may coexist. To increase the robustness of the long-lasting effects, we study randomized versions of CR stimulation in networks of leaky integrate-and-fire neurons with STDP. Randomization is obtained by adding random jitters to the stimulation times and by shuffling the sequence of stimulation site activations. We study the corresponding long-lasting effects using analytical calculations and computer simulations. We show that random jitters increase the robustness of long-lasting effects with respect to changes of the number of stimulation sites and the stimulation frequency. In contrast, shuffling does not increase parameter robustness of long-lasting effects. Studying the relation between acute, acute after-, and long-lasting effects of stimulation, we find that both acute after- and long-lasting effects are strongly determined by the stimulation-induced synaptic reshaping, whereas acute effects solely depend on the statistics of administered stimuli. We find that the stimulation duration is another important parameter, as effective stimulation only entails long-lasting effects after a sufficient stimulation duration. Our results show that long-lasting therapeutic effects of CR stimulation with random jitters are more robust than those of regular CR stimulation. This might reduce the parameter adjustment time in future clinical trials and make CR with random jitters more suitable for treating brain disorders with abnormal synchronization in multiple frequency bands.

The Effects of Intermittent Fasting on Brain and Cognitive Function.

The importance of diet and the gut-brain axis for brain health and cognitive function is increasingly acknowledged. Dietary interventions are tested for their potential to prevent and/or treat brain disorders. Intermittent fasting (IF), the abstinence or strong limitation of calories for 12 to 48 h, alternated with periods of regular food intake, has shown promising results on neurobiological health in animal models. In this review article, we discuss the potential benefits of IF on cognitive function and the possible effects on the prevention and progress of brain-related disorders in animals and humans. We do so by summarizing the effects of IF which through metabolic, cellular, and circadian mechanisms lead to anatomical and functional changes in the brain. Our review shows that there is no clear evidence of a positive short-term effect of IF on cognition in healthy subjects. Clinical studies show benefits of IF for epilepsy, Alzheimer’s disease, and multiple sclerosis on disease symptoms and progress. Findings from animal studies show mechanisms by which Parkinson’s disease, ischemic stroke, autism spectrum disorder, and mood and anxiety disorders could benefit from IF. Future research should disentangle whether positive effects of IF hold true regardless of age or the presence of obesity. Moreover, variations in fasting patterns, total caloric intake, and intake of specific nutrients may be relevant components of IF success. Longitudinal studies and randomized clinical trials (RCTs) will provide a window into the long-term effects of IF on the development and progress of brain-related diseases.

Nose-to-brain delivery of amisulpride-loaded lipid-based poloxamer-gellan gum nanoemulgel: In vitro and in vivo pharmacological studies

Unfavorable side effects of available antipsychotics limit the use of conventional delivery systems, where limited exposure of the drugs to the systemic circulation could reduce the associated risks. The potential of intranasal delivery is gaining interest to treat brain disorders by delivering the drugs directly to the brain circumventing the tight junctions of the blood–brain barrier with limited systemic exposure of the entrapped therapeutic. Therefore, the present research was aimed to fabricate, optimize and investigate the therapeutic efficacy of amisulpride (AMS)-loaded intranasal in situ nanoemulgel (AMS-NG) in the treatment of schizophrenia. In this context, AMS nanoemulsion (AMS-NE) was prepared by employing aqueous-titration method and optimized using Box-Behnken statistical design. The optimized nanoemulsion was subjected to evaluation of globule size, transmittance, zeta potential, and mucoadhesive strength, which were found to be 92.15 nm, 99.57%, −18.22 mV, and 8.90 g, respectively. The AMS-NE was converted to AMS-NG using poloxamer 407 and gellan gum. Following pharmacokinetic evaluation in Wistar rats, the brain Cmax for intranasal AMS-NG was found to be 1.48-folds and 3.39-folds higher when compared to intranasal AMS-NE and intravenous AMS-NE, respectively. Moreover, behavioral investigations of developed formulations were devoid of any extrapyramidal side effects in the experimental model. Finally, outcomes of the in vivo hematological study confirmed that intranasal administration of formulation for 28 days did not alter leukocytes and agranulocytes count. In conclusion, the promising results of the developed and optimized intranasal AMS-NG could provide a novel platform for the effective and safe delivery of AMS in schizophrenic patients.

The Medial Septum as a Potential Target for Treating Brain Disorders Associated With Oscillopathies.

The medial septum (MS), as part of the basal forebrain, supports many physiological functions, from sensorimotor integration to cognition. With often reciprocal connections with a broad set of peers at all major divisions of the brain, the MS orchestrates oscillatory neuronal activities throughout the brain. These oscillations are critical in generating sensory and emotional salience, locomotion, maintaining mood, supporting innate anxiety, and governing learning and memory. Accumulating evidence points out that the physiological oscillations under septal influence are frequently disrupted or altered in pathological conditions. Therefore, the MS may be a potential target for treating neurological and psychiatric disorders with abnormal oscillations (oscillopathies) to restore healthy patterns or erase undesired ones. Recent studies have revealed that the patterned stimulation of the MS alleviates symptoms of epilepsy. We discuss here that stimulus timing is a critical determinant of treatment efficacy on multiple time scales. On-demand stimulation may dramatically reduce side effects by not interfering with normal physiological functions. A precise pattern-matched stimulation through adaptive timing governed by the ongoing oscillations is essential to effectively terminate pathological oscillations. The time-targeted strategy for the MS stimulation may provide an effective way of treating multiple disorders including Alzheimer’s disease, anxiety/fear, schizophrenia, and depression, as well as pain.

Targeting the Gut to Treat the Brain.

Only ten years ago, the idea that bacteria in your gut could affect your brain and behavior was seen as a fringe theory. But today, it is well-established that the trillions of microbes in the gastrointestinal tract-collectively known as the gut microbiome-profoundly influence the brain. Now, researchers are working to harness the power of the gut microbiome to develop new treatments for brain disorders.

The Cannabis Constituent Cannabigerol Does Not Disrupt Fear Memory Processes or Stress-Induced Anxiety in Mice.

Introduction: Medicinal cannabis has proliferated around the world and there is increasing interest in the therapeutic potential of individual plant-derived cannabinoids (phytocannabinoids). Preclinical evidence suggests the phytocannabinoid cannabigerol (CBG) could be useful in treating brain disorders, including stress and anxiety-related disorders. In this study, we aimed to explore whether CBG disrupts various contextually conditioned fear memory processes and trauma-induced anxiety-related behavior in a mouse model of post-traumatic stress disorder (PTSD). Materials and Methods: All mice underwent contextual fear conditioning. CBG was administered between 1 and 60 mg/kg intraperitoneally (i.p.). We first assessed the effects of repeated CBG exposure on long-term fear memories. We also examined whether acute CBG affected various fear memory processes, namely expression, acquisition, consolidation, and reconsolidation of conditioned fear. Finally, the effect of acute CBG administration on stress-induced anxiety in the light/dark test was assessed. Results: Repeated CBG exposure did not affect long-term conditioned fear that was observed 24 days after the conditioning session. Moreover, acute CBG administration did not influence the acquisition, consolidation, reconsolidation, or expression of contextually conditioned fear. Acute CBG treatment also did not affect stress-induced anxiety-related behaviors in the light/dark test. Conclusions: CBG was ineffective in disrupting long-term fear memories, various conditioned fear memory processes, or stress-induced anxiety-related behavior in mice. These preclinical data suggest CBG may have limited scope in the treatment of PTSD and stress-related anxiety.

Restoring neuronal chloride homeostasis with anti-NKCC1 gene therapy rescues cognitive deficits in a mouse model of Down syndrome

A common feature of diverse brain disorders is the alteration of GABA-mediated inhibition because of aberrant, intracellular chloride homeostasis induced by changes in the expression and/or function of chloride transporters. Notably, pharmacological inhibition of the chloride importer NKCC1 is able to rescue brain-related core deficits in animal models of these pathologies and in some human clinical studies. Here, we show that reducing NKCC1 expression by RNA interference in the Ts65Dn mouse model of Down syndrome (DS) restores intracellular chloride concentration, efficacy of gamma-aminobutyric acid (GABA)-mediated inhibition, and neuronal network dynamics in vitro and ex vivo. Importantly, adeno-associated virus (AAV)-mediated, neuron-specific NKCC1 knockdown in vivo rescues cognitive deficits in diverse behavioral tasks in Ts65Dn animals. Our results highlight a mechanistic link between NKCC1 expression and behavioral abnormalities in DS mice and establish a molecular target for new therapeutic approaches, including gene therapy, to treat brain disorders characterized by neuronal chloride imbalance.