Manual therapy ameliorates neuromuscular dysfunction in spastic model rat: involvement of the C-Fiber-mediated CaMKII pathway

BackgroundThis study investigated whether manual therapy applied to tendon organs ameliorated neuromuscular dysfunction in rats with spasticity induced by upper motor neuron injury associated with spastic cerebral palsy, and analyzed the potential involvement of the C-fiber-mediated CaMKII signaling pathway.MethodsMale rats were used to establish palsy models and divided into groups: Control, Model, Manual Therapy (MT), Capsaicin Treatment, Sham, CaMKII Inhibitor, and DMSO Solvent groups. Except for Control, all underwent pyramidal-tract destruction. After modeling, the MT group received manual therapy on the left-lower leg tendon organs. The Capsaicin group underwent sciatic nerve capsaicin treatment for C-fiber block on days 2 and 7; the Sham group had sciatic nerve exposure only. Both received daily manual therapy intervention for 14 days. The CaMKII Inhibitor and DMSO Solvent groups received intrathecal injections every 2 days (7 times total) without manual intervention. Spasticity-related behavioral indices, molecular expression, and neurotransmitter levels were assessed.ResultsManual therapy reduced the neurological deficit scores and muscle spasticity scores of model rats, improved the pathological morphology of the pyramidal tract and skeletal muscle, and regulated the expression of key molecules and neurotransmitters in the spinal cord and hippocampus. The therapeutic effects of manual therapy were significantly attenuated after C-fiber blockage, and although CaMKII inhibition could partially mimic the neuromodulatory effects of manual therapy, its efficacy in alleviating spasticity was inferior to that of manual-therapy intervention.ConclusionManual therapy appears to regulate CaMKII signaling via C-fiber afferent pathways to ameliorate neuromuscular dysfunction in a rat model of spasticity induced by pyramidal-tract lesion, thereby providing experimental evidence for the clinical application of optimized manual therapy parameters in the management of spasticity in patients with cerebral palsy.

Dissociation: Signs and Causes in Children

When people use the word dissociation, it can sound alarming. You may have seen it on social media, heard your child mention it, or noticed your child seeming “checked out” and wondered if that’s what’s happening. Dissociation can be confusing because it exists on a spectrum — from everyday experiences like daydreaming to more serious symptoms that may signal that a child is overwhelmed or struggling. The good news is that dissociation is often a temporary coping mechanism, and when it does become a problem, there are effective ways to help.

What is dissociation?

In simple terms, dissociation is a kind of mental disconnection. “When I think of dissociation, I think of there being some sort of disconnect between an individual and their sense of self, or a period of time that you later can’t recall, or feeling like you’re disconnected from your body,” says Lauren Allerhand, PsyD, a clinical psychologist at the Child Mind Institute and co-director of its DBT program.

Some kids describe dissociation as feeling spaced out, numb, or disconnected from their body or surroundings. Others say they feel like they’re watching themselves from outside their body, or that the world around them doesn’t feel real. “There’s some period of time where your normal sense of flow is disrupted,” Dr. Allerhand explains.

Is dissociation normal?

In its mildest form, dissociation is a commonplace occurrence. Kids might daydream in class, zone out during something boring like a long car trip, or feel detached when they are overwhelmed in some way. These experiences are usually not a cause for concern. “Our brains do a really good job of protecting ourselves,” Dr. Allerhand says. “Sometimes our brains develop strategies to protect us that are healthy, and other times they develop strategies that might work in short bursts but become less helpful if they happen too much.”

When dissociation happens often, or interferes with daily life, it may signal that a child is struggling with something more serious than ordinary, intermittent stress. “If it’s happening all the time, it’s less effective as a coping mechanism” because of the toll it can take when there is memory loss, confusion, and feeling disconnected to the self, she explains.

What does dissociation feel like?

Children and teens may describe dissociation differently. Some say they feel:

  • Like they’re in a dream
  • Emotionally numb
  • Detached from their body
  • Like they’re watching themselves in a movie
  • Like things around them aren’t real

“Kids might say they feel like a robot. Everything feels fake around them,” Dr. Allerhand says. “Younger children may not have the words to describe what they’re experiencing. Instead, parents might notice their child seems unusually quiet, unresponsive, or ‘not themselves.’”

Why do kids dissociate?

Dissociation is often linked to stress or overwhelming emotions — kids may dissociate when they feel unable to cope with what’s happening around them. “This could be a response to any sort of highly intense emotion or experience,” Dr. Allerhand says, such as:

  • Trauma
  • Anxiety or panic
  • Intense emotions
  • Depression
  • Major life changes
  • Overwhelming stress

“It’s another way of coping with stress or trauma,” says Tanvi Bahuguna, PsyD, a clinical psychologist at the Child Mind Institute who specializes in trauma and mood disorders. “There’s this psychological process that helps them disconnect from overwhelming pain.” Some kids dissociate during panic attacks or periods of intense anxiety. Children who have experienced significant adversity may be more likely to dissociate. These experiences can include:

  • Abuse
  • Neglect
  • Family instability (housing instability, domestic violence, addiction)
  • Loss of a family member, especially through violence or suicide

Still, experts are quick to note that dissociation doesn’t automatically mean a child has experienced trauma or has a serious disorder. “There are lots of exits on this highway before we’re at a dissociative disorder,” Dr. Allerhand says, adding that a full-blown dissociative disorder is very rare in children.

Mild vs. serious dissociation

It can be hard to recognize when a child is experiencing more serious dissociation because it doesn’t always look different from daydreaming or inattention. One key difference is distress. “Spacing out or not paying attention is not often experienced as distressing,” Dr. Allerhand says. Moderate or serious dissociation “is often somewhat distressing.” Kids who are daydreaming are still connected to themselves and their surroundings; kids who are experiencing more serious dissociation may feel cut off from their body, emotions, or reality altogether.

Using grounding techniques for dissociation

If you think your child may be dissociating, the most important thing you can do is not panic or try to get your child to “snap out of it.”  “The number one thing a parent can do is stay as calm as possible,” Dr. Bahuguna says. Speak gently, use short sentences, and reassure your child that they’re safe. Saying your child’s name and reminding them you’re there can help them reconnect.

Grounding techniques can also bring kids back into the present moment. One common method is called the 5-4-3-2-1 technique: Ask the child to name five things they can see, four things they can feel, three things they can hear, two things they can smell, one thing they can taste or imagine tasting. Other grounding strategies include:

  • Deep breathing
  • Squeezing a stress ball
  • Holding something cold
  • Gently moving the body

If you find your child often dissociates, Dr. Allerhand recommends helping them make a plan for it. During a calm moment, talk with your child about what they find helpful. “I noticed that this is happening. How can I help you when this is happening?” she suggests asking. Having a plan in advance makes it easier to respond in the moment — and in the meantime, stay nearby and make sure your child is safe until the episode passes.

When should parents seek help for a child who dissociates?

If dissociation is frequent, distressing, or associated with changes in your child’s functioning, seeking professional support is appropriate. “If something dissociative happens, and there’s a really big change in your child’s functioning, then I would be concerned,” Dr. Allerhand says.

Signs it may be time to reach out include:

  • Memory gaps after the episode
  • Noticeable personality changes
  • Difficulty at school
  • Withdrawal from friends or activities
  • Significant distress or confusion

A good place to start would be talking to your pediatrician, who may refer you to a mental health professional. “If your child is displaying behaviors that seem out of the ordinary, you should trust your instincts,” Dr. Allerhand says.

How to identify dissociation

To determine whether a child is dissociating, a mental health professional gathers information from multiple sources, including parents, the child, and sometimes teachers, asking about the child’s behaviors, history, and any recent stressors or changes in behavior.

“The first thing would be a structured diagnostic interview with a qualified clinician,” Dr. Allerhand explains. “Parents bring the history and describe the behavior, and then the clinician meets with the child.” Clinicians also consider whether dissociation might be a symptom of another condition, such as post-traumatic stress disorder, borderline personality disorder, anxiety (especially panic disorder), and depression.

“It’s really gathering history, meeting the child, observing the child, and figuring out what this cluster of behaviors leads to,” she says. It’s more frequent to find that dissociation is a result of another disorder than an actual dissociative disorder.

How is dissociation treated?

Treatment depends on what’s driving the dissociation. If trauma is involved, therapy may focus on helping the child process difficult experiences and build coping skills. Evidence-based approaches include trauma-focused cognitive behavioral therapy (TF-CBT) and eye movement desensitization and reprocessing (EMDR).

If anxiety or emotional overwhelm is the primary cause, treatment may focus on emotion regulation, grounding techniques, and identifying triggers and early warning signs. Therapy, such as dialectical behavior therapy (DBT), typically involves both children and parents, helping families recognize patterns and respond in supportive ways.

For more severe or persistent dissociation, treatment may happen in phases — beginning with safety and stabilization, then skill-building, and eventually, when appropriate, processing difficult experiences. “The goal is helping the child learn to cope with their experience and stay in their body,” Dr. Allerhand says.

What are dissociative disorders?

In children and teens, dissociation is usually a symptom of another condition. But in cases of very serious early trauma, abuse, or neglect, it can progress into a full-blown disorder. There are a number of dissociative disorders, including:

  • Dissociative identity disorder (what was once called multiple personality disorder) involves two or more distinct personality states and gaps in memory and is typically linked to significant early trauma. Parents who search online may find alarming information, but Dr. Allerhand says this condition is very rare in kids.
  • Dissociative amnesia involves gaps in memory that can’t be explained by ordinary forgetfulness — such as not remembering important personal information or periods of time — and is often associated with stressful or traumatic experiences.
  • Depersonalization/derealization disorder involves feeling detached from oneself, as though watching yourself from outside your body, or feeling that the world around you isn’t real.

These disorders sometimes attract media attention, but they are extremely rare in children. What’s important for parents to know is that if you see dissociative behavior in a child, it’s most likely a normal coping mechanism for a child experiencing some stress or intense emotion. If it persists, is causing distress, or is interfering with a child’s life, it’s time to consult a pediatrician or mental health professional. Identifying what might be causing the behavior is the first step to getting appropriate treatment.

Frequently Asked Questions

What is dissociation?

Dissociation is a mental disconnection from your thoughts, feelings, body, or surroundings. Kids may feel spaced out, numb, or like they’re watching themselves from the outside, as if the world doesn’t feel real.

What are common symptoms of dissociation?

Common signs include feeling detached from the body, emotionally numb, or like you’re in a dream. Some kids seem unusually quiet or “not themselves,” while others have trouble recalling what happened during that time.

What causes dissociation?

Dissociation is often a response to stress, anxiety, or overwhelming emotions. It can also be linked to trauma, major life changes (such as the sudden loss of a family member), or intense feelings the child doesn’t yet know how to manage.

How can you stop dissociating?

Grounding techniques can help bring you back to the present moment, like naming what you see, hear, and feel, or focusing on breathing. Having a plan for what you will do the next time can make it easier to manage when it happens.

The post Dissociation: Signs and Causes in Children appeared first on Child Mind Institute.

Prostate Cancer Therapy Targets Disordered Region of Androgen Receptor

In a new study published in Nature Signal Transduction and Targeted Therapy titledDrugging the intrinsically disordered transactivation domain of androgen receptor,” researchers from the University of British Columbia and BC Cancer present a new approach for designing drugs that bind more strongly to intrinsically disordered proteins. These proteins play a central role in a wide range of diseases, including cancer, neurodegenerative disorders, heart disease and autoimmune conditions, and are extremely difficult to target due to their flexible nature.

Transactivation domains (TADs) of transcription factors are enriched in intrinsically disordered regions (IDRs) that lack a stable three-dimensional structure. The plasticity of an IDR permits dynamic conformations that regulate cellular and biological functions. 

The new study developed inhibitors that bound to the TADs of the androgen receptor, a therapeutic target for prostate cancer. While therapeutic interventions often target its folded ligand-binding domain (LBD), resistance ultimately develops due to reactivation of androgen receptor signaling. 

Inhibitors stabilized the protein in the inactive state to prevent the activation of genes that drive cancer growth. In animal studies, several compounds slowed prostate cancer growth more effectively than a commonly used prostate cancer treatment. Notably, several antigen receptor TAD inhibitors displayed strong binding affinities higher than, or were comparable to the LBD-inhibitor enzalutamide, with dissociation constants in the picomolar to low-nanomolar range 

“Most drug discovery is like designing a key for a very specific lock,” said Marianne Sadar, PhD, professor of pathology and laboratory medicine at the UBC faculty of medicine, distinguished scientist at BC Cancer, and co-corresponding author of the study. “But disordered proteins don’t behave like locks at all, they’re more like moving strands of spaghetti.”   

“This study shows that proteins previously thought to be undruggable can be drugged with remarkable efficacy,” she continued. “The findings could have profound implications for the treatment of cancer and other diseases, providing a roadmap for the development of new treatments.”   

“What surprised us was how effectively these molecules could attach to a protein that doesn’t have a fixed structure,” said Raymond Andersen, PhD, professor in UBC’s department of chemistry and co-corresponding author of the study. “We were able to shut down the androgen receptor even in situations where current prostate cancer drugs stop working.”   

The researchers now aim to advance the most promising candidates toward clinical trials, with the goal of developing prostate cancer drugs for early intervention and with fewer side-effects.  

“If the approach continues to prove successful, it could dramatically expand the number of proteins that scientists can target with medicines—turning what was once considered a dead end into a promising new frontier for drug discovery,” said Sadar. 

The post Prostate Cancer Therapy Targets Disordered Region of Androgen Receptor appeared first on GEN – Genetic Engineering and Biotechnology News.

Milnacipran continuation during pregnancy in a patient with severe post-traumatic stress disorder and psychotic depression: a case report with 3-year pediatric follow-up

Evidence on milnacipran exposure during pregnancy is sparse, complicating treatment decisions when maternal stability depends on this antidepressant. We report a 31-year-old primigravida with severe post-traumatic stress disorder and a severe major depressive episode with psychotic features in the context of a chronic, difficult-to-treat psychiatric course marked by self-harm, dissociation, and recurrent suicidal behavior. Milnacipran 150 mg/day led to marked clinical improvement before pregnancy. After pregnancy confirmation, treatment was changed to sertraline plus quetiapine because of limited pregnancy safety data, but depressive symptoms and suicidal behavior reemerged within 2 weeks. Milnacipran was therefore re-established after risk-benefit evaluation and shared decision-making, with renewed improvement. Moderate hyperemesis gravidarum during the second trimester led to discontinuation of milnacipran by gestational week 22. Delivery occurred at gestational week 38 via primary cesarean section. No congenital anomalies or neonatal adaptation problems were observed. At 3-year follow-up, pediatric developmental screenings remained within expected limits. This case illustrates the challenge of balancing relapse risk, prior treatment response, and treatment feasibility during pregnancy when evidence for the effective medication is limited.

Lithuanian children’s trauma characteristics and correlates: comparison of clinical and non-clinical samples

IntroductionPrevious studies have shown that children’s exposure to potentially traumatic events and their trauma−related symptoms may not always be consistently identified. This study aims to examine differences in trauma exposure and related psychological outcomes between clinical and non−clinical Lithuanian children.MethodsThis cross-sectional study included 10–17−year−old children and adolescents recruited from a clinical inpatient setting (Vilnius University Hospital Santaros Klinikos) and general−education schools in Vilnius and nearby districts. After parental consent and child assent, participants completed a secure mobile assessment covering exposure to potentially traumatic events (CATS), dissociation (A−DES), mood and feeling (SMFQ), post−traumatic cognitions (CPTCI), PTSD symptoms (CATS; PCL−5 for convergent validation), and perceived social support (CASSS). Data were collected in 2023–2024. Group differences were examined using Welch’s t−tests (with Mann–Whitney U as robustness checks), and associations were assessed using Pearson correlations.ResultsIn the clinical sample over 40% of children experienced physical violence, while in the non−clinical sample 82.9% children reported exposure to multiple traumatic events. The clinical sample showed significantly higher dissociation, negative mood, and PTSD symptoms compared to the non−clinical sample. However, among children exposed to more than one traumatic event, differences in dissociation, PTSD symptoms, and close−friend support were not significant. Across both samples, exposure to potentially traumatic events was strongly associated with PTSD symptoms, dissociation, and post−traumatic cognitions, and moderately associated with mood symptoms. In the non−clinical sample, parental support showed moderate negative associations with dissociation, mood symptoms, post−traumatic cognitions, and PTSD symptoms.DiscussionThis study identified between−sample differences in exposure to potentially traumatic events and trauma−related psychological outcomes among Lithuanian children in inpatient and community settings, highlighting the need for trauma−informed assessment and attention to social support within child mental health and welfare services.

Effect of low-intensity focused ultrasound on hippocampus of alcohol addicted mice: a preliminary study

Alcohol addiction is a chronic relapsing brain disorder characterized by significant neurobiological changes, particularly within the hippocampus, which mediates emotional regulation and reward-seeking behavior. Previous studies have shown that alcohol-induced neuronal injury contributes to withdrawal-associated anxiety and persistent alcohol preference. This study investigated the therapeutic effects of low-intensity focused ultrasound (LIFU) on the hippocampus in a mouse model of alcohol addiction. Twenty-six male C57BL/6 mice were allocated to an alcohol-exposed group (n = 20) and a control group (n = 6). Following a 28-day modeling period, the alcohol group was randomly subdivided into a therapy group and a sham group. The therapy group received LIFU treatment, while the sham group underwent an identical procedure with the ultrasound transducer powered off. After seven days of treatment, the therapy group exhibited less severe anxiety symptoms upon alcohol withdrawal and a reduced preference for alcohol compared to the sham group. The brain-derived neurotrophic factor (BDNF) concentration was significantly lower in the therapy group than in the sham group, but did not differ significantly from the control group. Hippocampal HE staining revealed more pronounced degeneration and apoptosis of granule cells in the dentate gyrus (DG) region in the sham group relative to the therapy group. These preliminary findings suggest that LIFU may modulate alcohol addiction by mitigating hippocampal neuronal injury.

Role of TRPC1 in the pathogenesis of depression induced by traumatic brain injury

BackgroundTraumatic brain injury (TBI) is one of the leading causes of mortality and disability, with many patients developing long-term sequelae. Depression is among the most common psychiatric complications following TBI, yet its underlying mechanisms remain unclear. Transient receptor potential canonical 1 (TRPC1) has been implicated in neurological disorders, but its role in post-TBI depression is not well understood.MethodsA controlled cortical impact (CCI) model was used to induce moderate TBI in mice. At 4 weeks post-injury, depressive-like behaviors were assessed using the tail suspension test (TST), forced swim test (FST), and sucrose preference test (SPT). Subsequently, reactive astrocytes and microglia were quantified, along with the expression of inflammatory cytokines, in the ipsilateral hippocampus. Synaptic function was also evaluated.ResultsBehavioral tests revealed that TBI mice exhibited significant depressive- and anxiety-like behaviors at 4 weeks post-injury. Concurrently, TRPC1 expression was downregulated in the ipsilateral hippocampus, accompanied by reduced levels of synaptic-associated proteins, elevated pro-inflammatory cytokines, and increased reactive astrocytes and microglia. Further experiments demonstrated that TRPC1 overexpression attenuated neuroinflammation, restored synaptic function, and ameliorated depressive-like behaviors in TBI mice.ConclusionThis study suggests that TBI may trigger depression by downregulating TRPC1, thereby promoting neuroinflammation and synaptic dysfunction. Conversely, TRPC1 overexpression mitigates these effects, highlighting its potential as a therapeutic target for post-TBI depression.

Diffusion tensor imaging-functional MRI fusion reveals disrupted white matter structure–function coupling in HIV-associated asymptomatic neurocognitive impairment

ObjectiveConventionally, blood oxygen level-dependent (BOLD) signals derived from resting-state functional magnetic resonance imaging (rs-fMRI) are attributed to gray matter, but recent evidence confirms stable low-frequency oscillations within white matter. While structure–function coupling is pivotal in neuropsychiatry, it remains underexplored in HIV-associated neurocognitive disorders (HAND). Focusing on Asymptomatic Neurocognitive Impairment (ANI), the earliest stage of HAND, this study establishes a white matter skeleton-based fusion framework integrating diffusion tensor imaging (DTI) and rs-fMRI to investigate underlying mechanisms.MethodsWe enrolled 47 patients with ANI and 48 matched healthy controls. Fractional anisotropy (FA) images from DTI and BOLD signals derived from rs-fMRI were projected onto a unified white matter skeleton to achieve structure–function spatial alignment. FA, skeleton-based white matter amplitude of low-frequency fluctuations (SWALFF), and its dynamic variability (dSWALFF) were calculated. Group differences in white matter structure and function were assessed, with structure–function coupling examined in regions showing overlapping FA-SWALFF and FA-dSWALFF alterations. Additionally, a novel White Matter Dys-coupling Index (WDI) was proposed to quantify the deviation between structural integrity and functional activity and evaluate its clinical relevance.ResultsCompared to controls, ANI patients exhibited widespread FA reductions and increased mean diffusivity (MD) and radial diffusivity (RD), indicating diffuse demyelination. Functionally, a spatial dissociation emerged: SWALFF was reduced in posterior occipital pathways (left vertical occipital fasciculus, forceps major), whereas SWALFF and dSWALFF were elevated in prefrontal pathways (forceps minor). Overlapping regions revealed complex coupling patterns, ranging from concordant decline to compensatory upregulation and decoupling. The interaction between FA and dSWALFF further highlighted instability in dynamic regulation. The WDI was significantly correlated with infection duration, immune status, and cognitive domain scores.ConclusionThis study identifies a characteristic “coupling imbalance” in the white matter of ANI patients, defined by the coexistence of structural degeneration and functional reorganization. We propose the WDI as a quantitative metric for this deviation. Its significant associations with clinical and cognitive metrics suggest its potential as a neuroimaging biomarker for the early identification and mechanistic understanding of HAND.