Hadar Shalev

Breaching the Blood-Brain Barrier as a Gate to Psychiatric Disorder

The mechanisms underlying the development and progression of psychiatric illnesses are only partially known. Clinical data suggest blood-brain barrier (BBB) breakdown and inflammation are involved in some patients groups. Here we put forward the “BBB hypothesis” and abnormal blood-brain communication as key mechanisms leading to neuronal dysfunction underlying disturbed cognition, mood, and behavior. Based on accumulating clinical data and animal experiments, we propose that events within the “neurovascular unit” are initiated by a focal BBB breakdown, and are associated with dysfunction of brain astrocytes, a local inflammatory response, pathological synaptic plasticity, and increased network connectivity. Our hypothesis should be validated in animal models of psychiatric diseases and BBB breakdown. Recently developed imaging approaches open the opportunity to challenge our hypothesis in patients. We propose that molecular mechanisms controlling BBB permeability, astrocytic functions, and inflammation may become novel targets for the prevention and treatment of psychiatric disorders.

Vascular Pathology and Blood-Brain Barrier Disruption in Cognitive and Psychiatric Complications of Type 2 Diabetes Mellitus

Vascular pathology is recognized as a principle insult in type 2 diabetes mellitus (T2DM). Co-morbidities such as structural brain abnormalities, cognitive, learning and memory deficits are also prevailing in T2DM patients. We previously suggested that microvascular pathologies involving blood-brain barrier (BBB) breakdown results in leakage of serum-derived components into the brain parenchyma, leading to neuronal dysfunction manifested as psychiatric illnesses. The current postulate focuses on the molecular mechanisms controlling BBB permeability in T2DM, as key contributors to the pathogenesis of mental disorders in patients. Revealing the mechanisms underlying BBB dysfunction and inflammatory response in T2DM and their role in metabolic disturbances, abnormal neurovascular coupling and neuronal plasticity, would contribute to the understanding of the mechanisms underlying psychopathologies in diabetic patients. Establishing this link would offer new targets for future therapeutic interventions.

Longitudinal associations between depression, anxiety, pain, and pain-related disability in chronic pain patients.

Objective The current study sets out to examine the longitudinal relationship between pain, pain-related disability, and symptoms of depression and anxiety. The latter symptoms are highly prevalent in chronic pain and seriously impede functioning and quality of life. Nevertheless, the direction of the relationship involving these variables among individuals with chronic pain is still unclear. Methods Four-hundred twenty-eight individuals with chronic pain (238 women, mean age 54.84 years, mean pain duration 85.21 months) treated at two pain clinics completed questionnaires regarding their pain (Short-Form McGill Pain Questionnaire), depression (Center for Epidemiological Studies–Depression Scale), state anxiety (State-Trait Anxiety Inventory), and pain-related disability (Pain Disability Index) at four time points, with an average of 5 months between measurements. Cross-lagged, structural equation modeling analyses were performed, enabling the examination of longitudinal associations between the variables. Results Significant symptoms of both depression and anxiety were reported by more than half of the sample on all waves. A latent depression/anxiety variable longitudinally predicted pain (&bgr; = .27, p < .001) and pain-related disability (&bgr; = .38, p < .001). However, neither pain (&bgr; = .10, p = .126) nor pain-related disability (&bgr; = −.01, p = .790) predicted depression/anxiety. Conclusions Among adult patients with chronic pain treated at specialty pain clinics, high levels of depression and anxiety may worsen pain and pain-related disability.

Blood-brain barrier dysfunction in brain diseases: clinical experience.

The blood–brain barrier, a unique feature of the cerebral vasculature, is gaining attention as a feature in common neurologic disorders including stroke, traumatic brain injury, epilepsy, and schizophrenia. Although acute blood–brain barrier dysfunction can induce cerebral edema, seizures, or neuropsychiatric symptoms, epileptogenesis and cognitive decline are among the chronic effects. The mechanisms underlying blood–brain barrier dysfunction are diverse and may range from physical endothelial damage in traumatic brain injury to degradation of extracellular matrix proteins via matrix metalloproteinases as part of an inflammatory response. Clinically, blood–brain barrier dysfunction is often detected using contrast‐enhanced imaging. However, these techniques do not give any insights into the underlying mechanism. Elucidating the specific pathways of blood–brain barrier dysfunction at different time points and in different brain diseases using novel imaging techniques promises a more accurate blood–brain barrier terminology as well as new treatment options and personalized treatment.

Traumatic stress is linked to a deficit in associative episodic memory

Individuals with posttraumatic stress disorder (PTSD) are haunted by persistent memories of the trauma, but ironically are impaired in memories of daily life. The current set of 4 experiments compared new learning and memory of emotionally neutral content in 2 groups of patients and aged- and education-matched controls: 20 patients diagnosed with chronic posttraumatic stress disorder (C-PTSD) and 20 patients diagnosed with acute stress disorder (ASD). In all experiments, participants studied a list of stimuli pairs (words or pictures) and were then tested for their memory of the items, or for the association between items in each pair. Results indicated that both types of patients showed associative memory impairment compared to a control group, although their item memory performance was relatively intact. Potential mechanisms underlying such associative memory deficits in posttraumatic patients are discussed.

Emotional Brain Rhythms and their Impairment in Post-Traumatic Patients

Patients with post‐traumatic stress disorder (PTSD) suffer from a failure of cognitive control over emotional distracters. The physiological substrates of cognitive‐emotional interactions and their breakdown in disease are, however, unknown. Here, we studied brain activity in PTSD patients and healthy controls in response to emotion‐provoking pictures using electroencephalography and functional magnetic resonance imaging (fMRI). We demonstrate that in healthy individuals, emotion‐induced frontal theta rhythm modulates activity in the beta rhythm mainly in sensory‐motor regions. In contrast, in PTSD patients, beta activity is elevated irrespective of emotion, and is not modulated by frontal theta activity in response to negative emotion. EEG source localization and fMRI findings suggest that theta activity is localized to the prefrontal and anterior cingulate cortices while beta activity is localized to sensory‐motor regions. We further found that beta activity in sensory‐motor regions is related to the emotion‐induced slowing of the motor response in healthy controls while the excess frontal theta activity in PTSD is related to the intensity of negative emotional experience. These findings reveal for the first time the importance of brain electrical oscillations and coherence in emotional top‐down modulation and point to specific failure of these mechanisms in PTSD. Hum Brain Mapp, 2013.

Obstetric and perinatal outcomes in women with eating disorders.

BACKGROUND We wished to investigate whether women with a history of eating disorders have an increased risk for adverse obstetric and perinatal outcomes. STUDY DESIGN A retrospective study was conducted comparing pregnancy complications in patients with and without eating disorders. Deliveries occurred during the years 1988-2009 in a tertiary medical center. Women lacking prenatal care and with multiple gestations were excluded from the study. Stratified analyses were performed using multivariable logistic regression models. Odds ratios (OR) and their 95% confidence interval (CI) were computed. A p value<0.05 was considered statistically significant. RESULTS During the study period, of 117,875 singleton deliveries, 122 (0.1%) occurred in patients with eating disorders. Eating disorders were significantly associated with fertility treatments (5.7% vs. 2.8%, p=0.047), intrauterine growth restriction (7.4% vs. 2.3%, p<0.001), term low birth weight (<2500 g) (7.4% vs. 2.8%, p=0.002), preterm delivery (15.6% vs. 7.5%, p=0.002), and cesarean delivery (25.4% vs. 15.0%, p=0.001). Using multivariable analyses, low birth weight (OR 2.5, 95% CI 1.3-5.0), preterm delivery (OR 2.2, 95% CI 1.4-3.6), and cesarean section (OR 1.9, 95% CI 1.3-2.9) were significantly associated with eating disorders. CONCLUSIONS Eating disorders are associated with increased risk of adverse pregnancy outcomes. Accordingly, careful surveillance is needed for early detection of possible complications.

Associative memory impairment in acute stress disorder: Characteristics and time course

Stress and episodic memory impairment have previously been associated. Acute stress disorder (ASD) is a maladaptive stress response, which develops in some individuals following traumatic life events. Recently, the authors demonstrated a specific deficit in associative memory for emotionally neutral stimuli in ASD and posttraumatic stress disorder (PTSD). This study further tested the relationship between this memory impairment and the course of ASD. We assessed new learning and memory for item and associative information in patients diagnosed with ASD (n=14) and matched trauma naïve controls (n=14). Memory performance and posttraumatic symptoms were examined for approximately 1 and 10 week periods following the traumatic experience. In the two experiments, participants studied a list of stimuli pairs (verbal or visual) and were then tested for their memory of the items (item recognition test), or for the association between items in each pair (associative recognition test). In both experiments, ASD patients showed a marked associative memory deficit compared to the control group. After 10 weeks, ASD symptoms were resolved in most patients. Interestingly, their performance on associative recognition for verbal stimuli improved, while the associative deficit for visual stimuli remained unchanged. Potential mechanisms underlying such an associative memory deficit in post-trauma patients are discussed.

Stress-induced altered cholinergic-glutamatergic interactions in the mouse hippocampus.

Psychological stress may lead to long-lasting brain dysfunction, specifically altered emotional and cognitive capabilities. Previous studies have demonstrated persistent changes in the expression of key cholinergic genes in the neocortex and hippocampus following stress with muscarinic receptor-mediated enhanced excitability. In the present study we examined cholinergic-mediated glutamatergic transmission in the hippocampus of mice after exposure to stress and its potential role in synaptic plasticity and altered behavior. Adult male mice were tested one month after repeated forced swimming test. Non-treated age-matched animals served as controls. Electrophysiological recordings were performed in the acute in-vitro slice preparation. CA1 pyramidal neurons were recorded using whole cell patch configuration. Extracellular recordings were done in response to Shaffer collaterals (SC) or stratum orien (SO) stimulation. Animal behavior in response to inhibition of acetylcholinesterase (AChE) was tested in open field paradigms. In whole cell patch recordings the frequency of excitatory post-synaptic currents (EPSCs) was significantly increased in response to muscarinic activation in stress-exposed animals. This enhanced cholinergic-modulated excitatory transmission is associated with facilitation of long-term potentiation (LTP) in response to tetanic stimulation at the SO but not at the SC. Stress-related behavioral modulation via central cholinergic pathways was enhanced by the central AChE inhibitor, physostigmine, thus further supporting the notion that stress is associated with long lasting hypersensitivity to acetylcholine. Our results revealed a pathway-specific enhancement of cholinergic-dependent glutamatergic transmission in the hippocampus after stress. These changes may underlie specific hippocampal malfunction, including cognitive and emotional disturbances, as observed in patients with post-traumatic stress disorder (PTSD).

Breakdown of Inter-Hemispheric Connectivity Is Associated with Posttraumatic Symptomatology and Memory Impairment

Altered brain anatomy in specific gray-matter regions has been shown in patients with posttraumatic stress disorder (PTSD). Recently, white-matter tracts have become a focus of research in PTSD. The corpus callosum (CC) is the principal white-matter fiber bundle, crucial in relaying sensory, motor and cognitive information between hemispheres. Alterations in CC fibers have been reported in PTSD and might be assumed to underlie substantial behavioral and cognitive sequelae; however most diffusion tensor imaging (DTI) studies in adult-onset PTSD failed to address the clinical correlates between imaging and PTSD symptoms severity, behavioral manifestation and cognitive functions. In the current study we examined (a) to what extent microstructural integrity of the CC is associated with memory performance and (b) whether imaging and cognitive parameters are associated with PTSD symptom severity. DTI data were obtained and fractional anisotropy (FA) values were computed for 16 patients and 14 controls. PTSD symptom severity was assessed by employing the clinician administered PTSD scale (CAPS) and memory was tested using a task probing item and associative memory for words and pictures. Significant correlations were found between PTSD symptoms severity, memory accuracy and reaction-time to CC FA values in the PTSD group. This study demonstrates meaningful clinical and cognitive correlates of microstructural connectivity. These results have implications for diagnostic tools and future studies aimed at identifying individuals at risk for PTSD.