Nosakhare N. Ekhator

Elevated Cerebrospinal Fluid Substance P Concentrations in Posttraumatic Stress Disorder and Major Depression

OBJECTIVE The authors tested the hypothesis that concentrations of the pain-transmitting neuropeptide substance P are elevated in the CSF of patients with major depression or posttraumatic stress disorder (PTSD), which have overlapping symptoms. The authors also sought to determine if CNS substance P concentrations change on provocation of symptoms in PTSD patients. METHOD The authors measured CSF substance P concentrations in medication-free patients with either major depression or PTSD and in healthy comparison subjects. Next, using a within-subject, crossover design, the authors sampled CSF for 6 hours through an indwelling subarachnoid catheter in PTSD patients before, during, and after exposure to a 60-minute traumatic or neutral videotape stimulus. RESULTS Both depressed and PTSD patients had significantly elevated basal CSF substance P concentrations. In the challenge study, marked increases in CSF substance P concentrations were found only after precipitation of PTSD symptoms. CSF substance P concentrations increased by 169% and 90.6% of baseline levels at 10 and 70 minutes, respectively, after the start of the traumatic videotape but changed by only 1.1% and -8.1% of baseline levels 10 and 70 minutes after the start of the neutral videotape. CONCLUSIONS These results suggest that elevated CNS substance P concentrations are involved in both major depression and PTSD. The marked increase in CSF substance P concentrations during and after the symptom-provoking stimulus, but not after the neutral stimulus, implicates CNS release of substance P in the mechanism of acute PTSD symptoms. These data also reveal that CNS substance P responds acutely to psychological stress in humans.

Low Cerebrospinal Fluid Neuropeptide Y Concentrations in Posttraumatic Stress Disorder

BACKGROUND Neuropeptide Y (NPY), a peptide neurotransmitter that regulates stress and anxiety, has been proposed to be a stress resilience factor in humans. Posttraumatic stress disorder (PTSD) is a stress-related anxiety disorder. We hypothesized that central nervous system NPY is dysregulated in PTSD and sought to redress the absence of central NPY data in the disorder. METHODS We determined morning NPY concentrations in cerebrospinal fluid (CSF) from 10 male subjects with chronic combat-related PTSD and from 13 healthy men. Neuropeptide Y-like immunoreactivity was measured by enzyme immunoassay (EIA). RESULTS As compared with the normal comparison subjects, PTSD patients had significantly lower concentrations of CSF neuropeptide Y (mean CSF NPY was 360.0 +/- 17.7 pg/mL in control subjects but only 233.6 +/- 28.7 pg/mL in PTSD patients [p = .0008]). Adjustments for age and body mass index (BMI) still revealed a highly significant reduction in CSF NPY in the PTSD group (p = .003). CONCLUSIONS Men with combat-related PTSD have low CSF concentrations of the putative resiliency hormone NPY, possibly related to the disorder or to extreme stress exposure per se.

Effects of trauma-related audiovisual stimulation on cerebrospinal fluid norepinephrine and corticotropin-releasing hormone concentrations in post-traumatic stress disorder

BACKGROUND Although elevated concentrations of both corticotropin-releasing hormone (CRH) and norepinephrine are present in the cerebrospinal fluid (CSF) of patients with post-traumatic stress disorder (PTSD), the effects of exposure to traumatic stimuli on these stress-related hormones in CSF are unknown. METHODS A randomized, within-subject, controlled, cross-over design was used, in which patients with war-related PTSD underwent 6-h continuous lumbar CSF withdrawal on two occasions per patient (6-9 weeks apart). During one session the patients watched a 1-h film containing combat footage (traumatic film) and in the other a 1-h film on how to oil paint (neutral film). At 10-min intervals, we quantified CRH and norepinephrine in CSF, and ACTH and cortisol in plasma, before, during, and after symptom provocation. Subjective anxiety and mood were monitored using 100-mm visual analog scales. Blood pressure and heart rate were obtained every 10min from a left leg monitor. RESULTS Eight of 10 patients completed two CSF withdrawal procedures each. A major drop in mood and increases in anxiety and blood pressure occurred during the traumatic relative to the neutral videotape. CSF norepinephrine rose during the traumatic film relative to the neutral videotape; this rise directly correlated with magnitude of mood drop. In contrast, CSF CRH concentrations declined during the trauma-related audiovisual stimulus, both absolutely and relative to the neutral stimulus; the magnitude of CRH decline correlated with degree of subjective worsening of anxiety level and mood. Plasma cortisol concentrations were lower and ACTH levels similar during the stress compared with the neutral videotape. CONCLUSIONS CSF concentrations of the stress hormones norepinephrine and CRH differentially change after exposure to 1h of trauma-related audiovisual stimulation in chronic, combat-related PTSD. While the CSF norepinephrine increase was postulated, the decline in CSF CRH levels is surprising and could be due to audiovisual stress-induced increased uptake of CSF CRH into brain tissue, increased CRH utilization, increased CRH degradation, or to an acute stress-related inhibition or suppression of CRH secretion.

Low cerebrospinal fluid and plasma orexin-A (hypocretin-1) concentrations in combat-related posttraumatic stress disorder

The hypothalamic neuropeptide, orexin-A has a number of regulatory effects in humans and pre-clinical evidence suggests a link to neuroendocrine systems known to be pathophysiologically related to posttraumatic stress disorder (PTSD). However, there are no reports of central nervous system (CNS) or peripheral orexin-A concentrations in patients with PTSD, or any anxiety disorder. Cerebrospinal fluid (CSF) and plasma levels of orexin-A were serially determined in patients with PTSD and healthy comparison subjects to characterize the relationships between orexin-A (in the CNS and peripheral circulation) and central indices of monoaminergic neurotransmission and to determine the degree to which CNS orexin-A concentrations reflect those in the circulating blood. CSF and plasma samples were obtained serially over a 6-h period in 10 male combat veterans with chronic PTSD and 10 healthy male subjects through an indwelling subarachnoid catheter. Orexin-A concentrations were determined in plasma and CSF and CSF levels of the serotonin metabolite, 5-hydroxyindolacetic acid (5-HIAA), and the dopamine metabolite, homovanillic acid (HVA), were determined over the sampling period. CSF and plasma orexin-A concentrations were significantly lower in the patients with PTSD as compared with healthy comparison subjects at all time points. In addition, CSF orexin-A concentrations strongly and negatively correlated with PTSD severity as measured by the Clinician-Administered PTSD Scale (CAPS) in patients with PTSD. Peripheral and CNS concentrations of orexin-A were correlated in the healthy comparison subjects and peripheral orexin-A also correlated with CNS serotonergic tone. These findings suggest low central and peripheral orexin-A activity in patients with chronic PTSD are related to symptom severity and raise the possibility that orexin-A is part of the pathophysiological mechanisms of combat-related PTSD.

Cerebrospinal fluid neuropeptide Y in combat veterans with and without posttraumatic stress disorder

Accruing evidence indicates that neuropeptide Y (NPY), a peptide neurotransmitter, is a resilience-to-stress factor in humans. We previously reported reduced cerebrospinal fluid (CSF) NPY concentrations in combat-related posttraumatic stress disorder (PTSD) subjects as compared with healthy, non-combat-exposed volunteers. Here we report CSF NPY in combat-exposed veterans with and without PTSD. We quantified NPY concentrations in morning CSF from 11 male subjects with PTSD from combat in Iraq and/or Afghanistan and from 14 combat-exposed subjects without PTSD. NPY-like immunoreactivity (NPY-LI) was measured by EIA. The relationship between CSF NPY and clinical symptoms, as measured by the Clinician-Administered PTSD Scale (CAPS) and Beck Depression Inventory (BDI), was assessed, as was the relationship between combat exposure scale (CES) scores and CSF NPY. As compared with the combat-exposed comparison subjects without PTSD, individuals with PTSD had significantly lower concentrations of CSF NPY [mean CSF NPY was 258. 6 ± 21.64 pg/mL in the combat trauma-no PTSD group but only 180.5 ± 12.62 pg/mL in PTSD patients (p=0.008)]. After adjusting for CES and BDI scores the two groups were still significantly different with respect to NPY. Importantly, CSF NPY was negatively correlated with composite CAPS score and intrusive (re-experiencing) subscale scores, but did not significantly correlate with CES or BDI scores. Our current findings further suggest that NPY may regulate the manifestation of PTSD symptomatology, and extend previous observations of low CSF NPY concentrations in the disorder. Central nervous system NPY may be a clinically important pharmacotherapeutic target, and/or diagnostic measure, for PTSD.

Pituitary-Thyroid State Correlates with Central Dopaminergic and Serotonergic Activity in Healthy Humans

Data from lower animals suggest anatomic and physiological interactions between brain dopamine and serotonin (5-hydroxytryptamine, 5-HT) systems and the hypothalamic-pituitary-thyroid axis. However, in humans, investigations of interactions between these central neurochemical systems (especially the dopaminergic system) and thyroid function are rare; in healthy humans they are practically nonexistent. Using cerebrospinal fluid (CSF) and blood samples simultaneously obtained from indwelling subarachnoid and venous catheters in healthy humans, we determined the CSF concentrations of homovanillic acid (HVA) and 5-hydroxyindolacetic acid, the major metabolites of dopamine and 5-HT, and plasma concentrations of TSH, total triiodothyronine (T3), free T3, total thyroxine (T4) and free T4. CSF HVA concentrations were significantly and negatively correlated with plasma TSH and T3 (free and total), but not with T4 (free or total). CSF 5-HIAA concentrations were significantly and negatively correlated with plasma TSH and total T3 but not with free T3 or T4 (free or total). These results indicate that CNS monoamine-thyroid interactions are of physiological significance in the normal, euthyroid human.

Blood pressure and cerebrospinal fluid norepinephrine in combat-related posttraumatic stress disorder

Objective: Central nervous system norepinephrine (NE) is normally involved in blood pressure regulation, but it is pathophysiologically elevated in posttraumatic stress disorder (PTSD). Methods: We monitored blood pressure while performing serial cerebrospinal fluid (CSF) sampling for 6 hours to determine CSF NE concentrations in men with combat-related PTSD (n = 11) and in healthy men (n = 8). Results: CSF NE concentrations strongly and positively correlated with mean diastolic blood pressure in the healthy men (R = 0.93, p < .002) but not in the patients (R = 0.10, p = .77). Within individuals, mean arterial pressure, systolic blood pressure, diastolic blood pressure and pulse pressure were poorly correlated over time in patients with PTSD but highly correlated over time in the healthy men, indicating that measurement of these hemodynamic parameters are poorly prognostic of subsequent measurements of the same parameter in patients with PTSD. Conclusion: These data demonstrate the loss of the normal direct relationship between CSF NE and blood pressure in combat veterans with PTSD. Whether this dysynchrony mechanistically relates to the hemodynamic abnormalities in PTSD or, like some of the psychobehavioral symptoms, can be corrected with anti-noradrenergic pharmacotherapy remains to be determined. NE = norepinephrine; CNS = central nervous system; PTSD = posttraumatic stress disorder; CSF = cerebrospinal fluid; MAP = mean arterial pressure; BMI = body mass index; AR = autoregressive order 1 model.

In-use stability of monoamine metabolites in human cerebrospinal fluid

Cerebrospinal fluid (CSF) concentrations of the monoamine metabolites homovanillic acid (HVA) and 5-hydroxyindolacetic acid (5-HIAA) are commonly used to provide information about central nervous system (CNS) dopaminergic and serotonergic activity. However, little attention has been given to the effects of sample handling on the concentrations of these compounds in human CSF. Using high-performance liquid chromatography (HPLC) with electrochemical detection, we observed that, in CSF stored at -80 degrees C, concentrations of the serotonin metabolite 5-HIAA and the dopamine metabolite HVA remained unchanged through six 1-h and six 24-h freeze-thaw cycles. Exposure to bright room light (3 h, 1,230 lux) resulted in a 5-HIAA concentration that was 96.3 +/- 2.0% of the initial and an HVA concentration that was 98.8 +/- 1.03% of initial. The pH of the CSF significantly increased during both freeze-thaw series and while maintained on ice (4 degrees C). These results demonstrate the in-use stability of 5-HIAA and HVA in human CSF under commonly-encountered laboratory conditions.

Intra- and inter-individual relationships between central and peripheral serotonergic activity in humans: a serial cerebrospinal fluid sampling study

Data are lacking concerning the longitudinal covariability and cross-sectional balance between central and peripheral 5-HIAA concentrations in humans and on the possible associations between tobacco smoking or post-traumatic stress disorder (PTSD) and CSF and plasma 5-HIAA concentrations. Using serial cerebrospinal fluid (CSF) and blood sampling, we determined the concentrations of 5-HIAA in CSF and plasma over 6 h, and examined their relationships in healthy volunteers and patients with PTSD-both smokers and nonsmokers. Patients with PTSD and healthy volunteers had very similar CSF 5-HIAA concentrations. Significant and positive correlations between CSF and plasma 5-HIAA levels were observed within individuals, but this CNS-peripheral 5-HIAA relationship was significantly reduced in smokers (nonsmokers: mean r = 0.559 +/- 0.072; smokers: mean r = 0.329 +/- 0.064 p < 0.038). No significant cross-sectional, interindividual correlation of mean CSF and mean plasma 5-HIAA was seen (r = 0.094). These data show that changes in CSF 5-HIAA levels within an individual over time are largely reflected in plasma 5-HIAA, albeit significantly less so in smokers. The present results therefore suggest that clinically, longitudinal determination of plasma 5-HIAA concentrations within an individual patient can be used to make inferences about relative changes in integrated CSF 5-HIAA concentrations. However, plasma 5-HIAA concentrations provide no significant information about absolute levels of the serotonin metabolite in the CSF.

The effect of feeding on cerebrospinal fluid corticotropin-releasing hormone levels in humans.

Corticotropin-releasing hormone (CRH) is a neuropeptide thought to play a role in appetite regulation. In this report, we used a serial cerebrospinal fluid (CSF) sampling technique to examine the relationship between CSF CRH, plasma ACTH and cortisol and perceptions of hunger and satiety in fasting and sated volunteers. CSF was withdrawn continuously from 11:00 AM to 5:00 PM via an indwelling subarachnoid catheter. Blood was withdrawn every 10 min via an antecubital vein catheter. Fed subjects received a meal at 1:00 PM. Subjects who were fed had lower post-prandial ratings on hunger scales and higher ratings on satiety scales. Fed subjects also had slightly lower levels of CSF CRH after feeding. Furthermore, fed subjects had higher ACTH and cortisol concentrations in the first 3 h; by the fourth h the opposite was true. Our findings do not support the hypothesis that CNS CRH is a central satiety factor in the human. Instead our findings of slightly diminished CSF CRH levels after feeding may be accounted for by the rises in glucocorticoids and their associated negative feedback effects on CNS CRH. Alternatively, our findings could also reflect changes in CRH levels associated with feeding in multiple brain areas and in the spinal cord with the net effect being in the negative direction.