Triple stimulation technique findings in vascular Parkinsonism and Parkinson’s disease

ObjectiveOne of the predominant clinical features that differentiates vascular Parkinsonism (VP) from Parkinson’s disease (PD) is the pyramidal sign. The triple stimulation technique (TST) is one of the most sensitive methods for comparing upper motor neuron involvement in patients with VP and PD. This study aimed to evaluate the usefulness of the TST as a diagnostic tool for VP.MethodsThirteen VP patients, 18 PD patients and 10 age-matched healthy controls were enrolled in this study. We obtained basic participant demographic information and transcranial magnetic stimulation (TMS) parameters, including the TST amplitude ratio, from all participants. We compared the TMS parameters among the VP, PD and control groups.ResultsThe TST amplitude ratio was significantly lower in the VP group than in the PD and control groups (71.59 ± 11.86 vs. 96.42 ± 5.11 and 97.70 ± 3.82, respectively; p < 0.01). The TST amplitude ratio was positively correlated with scores obtained on the United Parkinson’s Disease Rating Scale-III, which reflects motor function.ConclusionsThe TST is an effective and easy technique that offers improved diagnostic sensitivity in patients with VP by assessing upper motor neuron involvement. The TST may also represent a useful monitoring tool for evaluating disease progression.SignificanceThis study is the first to assess pyramidal involvement in patients with VP using the collision technique.     

The glial activation inhibitor AV411 reduces morphine-induced nucleus accumbens dopamine release

Glial activation has recently been discovered to modulate several effects of morphine, including analgesia, tolerance, and dependence. The present studies extend this line of investigation by exploring whether glial activation may also affect extracellular levels of dopamine (DA) in the nucleus accumbens (NAc) shell, a neurochemical corollary of morphine-induced drug reward, during a challenge dose of morphine in experiments both with and without precipitated withdrawal. Morphine or vehicle was administered s.c. for 4 days (starting at 15 mg/kg/day up to 20 mg/kg/day), and the glial activation inhibitor AV411 (7.5 mg/kg) or vehicle was administered twice daily. A challenge dose of morphine (22.5 mg/kg) or saline was then given during dialysis. In the first experiment, naloxone (10 mg/kg) was administered 1 h after morphine during dialysis in AV411- or vehicle-treated rats, and behavioral signs of somatic withdrawal were assessed during microdialysis. In the second experiment, using the same dosing regimen, sampling continued 3 h after morphine or saline in AV411- or vehicle-treated rats. NAc DA increased in vehicle-treated rats significantly more than in AV411-treated rats before naloxone treatment, and withdrawal symptoms were significantly reduced in AV411-treated rats. The decrease in morphine-induced NAc DA by AV411 was persistent, lasting 3+ h post-morphine. These results indicate that glial activation contributes to the effects of morphine on NAc DA, which is associated with somatic signs of precipitated withdrawal.     

Intraduodenal levodopa-carbidopa intestinal gel infusion improves both motor performance and quality of life in advanced Parkinson’s disease

We report the efficacy and adverse effect profile of intraduodenal levodopa-carbidopa intestinal gel (LCIG) infusion from patients treated in a single Australian movement disorder centre. We conducted an open-label, 12 month prospective study of treatment with LCIG in patients with advanced Parkinson’s disease in a single tertiary referral hospital unit specialising in movement disorders. Patients with levodopa-responsive, advanced Parkinson’s disease with motor fluctuations despite optimal pharmacological treatment were enrolled and underwent a 16 hour daily infusion of LCIG for 12 months. Fifteen participants completed the trial. The mean (±standard deviation) improvement in Unified Parkinson’s Disease Rating Scale part III was 37 ± 11%, mean daily “off” period reduced from 6.3 ± 2 to 1.9 ± 2 hours, total daily “on” time increased from 10.2 ± 3 to 13.7 ± 2 hours, “on” period without dyskinesia increased from 4.5 ± 3 to 7.5 ± 5 hours, and 39-item Parkinson’s Disease Questionnaire Summary Index score improved by 32.5 ± 35%. The most common adverse event was reversible peripheral neuropathy secondary to vitamin B12 ± B6 deficiency (40%), local tube problems (40%), and impulse control disorder (ICD) (27%). No patient had stoma bleeding or peritonitis. All patients with ICD had a past psychiatric diagnosis of depression with or without anxiety and a higher daily levodopa intake at 6 and 12 months of LCIG infusion. Intraduodenal LCIG improves motor performance, quality of life and daily “on” period. Prior to and during duodenal LCIG infusion, clinicians should monitor for peripheral neuropathy and vitamin B12 and B6 deficiency, as supplementation can reverse peripheral neuropathy. This trial is registered at Clinicaltrials.gov as CT00335153.     

Dose response effect of methylphenidate on ventral tegmental area neurons and animal behavior

Methylphenidate (MPD) is the drug of choice prescribed to treat ADHD patients. More recently, MPD is also used as a cognitive enhancement and recreationally by young adults and its therapeutic effects are not fully understood. One of the neuroanatomical sites is reported to be the ventral tegmental area (VTA). The ventral tegmental area neuronal activity was recorded from freely behaving non-anesthetized rats implanted bilaterally with semi-permanent electrodes which were recorded from a wireless telemetric system. Thirty-three animals, divided randomly into four groups, were used: saline (n = 10), 0.6 mg/kg (n = 6), 2.5 mg/kg (n = 7) and 10.0 mg/kg MPD (n = 10). MPD caused an increase in locomotor activity with a dose response characteristic; 0.6 mg/kg MPD elicited some increase in locomotion, but not significantly, while 2.5 and 10.0 mg/kg MPD elicited significant increases in behavior of 191% and 870% respectively. A total of 209 ventral tegmental area units were recorded; 100% (36/36) units showed no response to saline; 89% (154/173) of the neurons responded to MPD, with the majority 66% (101/154) showing an increase in activity. In response to 0.6 mg/kg (n = 52), the majority of units 54% (28/52) showed a decrease in activity. For both 2.5 (n = 60) and 10.0 mg/kg (n = 61), the majority of ventral tegmental area units responded with an increase in activity with 63% (38/60) and 70% (43/61) respectively. This study demonstrated that the majority of ventral tegmental area neurons respond to acute MPD in a dose response characteristic and are not related to the animal's locomotor activity.     

Calorie restriction dose-dependently abates lipopolysaccharide-induced fever,sickness behavior,and circulating interleukin-6 while increasing corticosterone

In mice a 50% calorie restriction (CR) for 28 days attenuates sickness behavior after lipopolysaccharide (LPS) and these mice demonstrate a central anti-inflammatory bias. This study examined the dose-dependent effect of CR on sickness behavior (fever, anorexia, cachexia) and peripheral immune markers post-LPS. Male Sprague–Dawley rats fed ad libitum or CR by 50% for 14, 21, or 28 days were injected on day 15, 22, or 29 with 50 μg/kg of LPS or saline (1 mL/500 g). Changes in body temperature (T_b), locomotor activity, body weight, and food intake were determined. A separate cohort of rats was fed ad libitum or CR by 50% for 28 days and serum levels of corticosterone (CORT), interleukin 6 (IL-6), and IL-10 were determined at 0, 2, and 4 h post-LPS. The rats CR for 28 days demonstrated the largest attenuation of sickness behavior: no fever, limited reduction in locomotor activity, no anorexia, and reduced cachexia following LPS. Rats CR for 14 and 21 days demonstrated a partial attenuation of sickness behavior. Rats CR for 14 days demonstrated a larger increase in T_b, larger reduction in locomotor activity, and larger weight loss compared to rats CR for 21 days. Serum CORT was increased at 2 h post-LPS in ad libitum and CR groups; however it was two times larger in the CR animals. Levels of IL-6 were significantly attenuated at 2 h post-LPS in the CR animals. IL-10 levels were similar post-LPS. CR results in an enhanced anti-inflammatory response in the form of increased CORT and diminished pro-inflammatory signals.     

Corneal nerve microstructure in Parkinson’s disease

Ocular surface changes and blink abnormalities are well-established in Parkinson’s disease. Blink rate may be influenced by corneal sub-basal nerve density, however, this relationship has not yet been investigated in Parkinson’s disease. This case-control study examined the ocular surface in patients with moderately severe Parkinson’s disease, including confocal microscopy of the cornea. Fifteen patients with moderately severe Parkinson’s disease (modified Hoehn and Yahr grade 3 or 4) and fifteen control participants were recruited. Ophthalmic assessment included slit-lamp examination, blink rate assessment, central corneal aesthesiometry and in vivo corneal confocal microscopy. The effect of disease laterality was also investigated. Of the 15 patients with Parkinson’s disease, ten were male and the mean age was 65.5 ± 8.6 years. The corneal sub-basal nerve plexus density was markedly reduced in patients with Parkinson’s disease (7.56 ± 2.4 mm/mm²) compared with controls (15.91 ± 2.6 mm/mm²) (p < 0.0001). Corneal sensitivity did not differ significantly between the patients with Parkinson’s disease (0.79 ± 1.2 mBAR) and the control group (0.26 ± 0.35 mBAR), p = 0.12. Sub-basal nerve density was not significantly different between the eye ipsilateral to the side of the body with most-severe motor symptoms, and the contralateral eye. There was a significant positive correlation between ACE-R scores and sub-basal corneal nerve density (R² = 0.66, p = 0.02). This is the first study to report a significant reduction in corneal sub-basal nerve density in Parkinson’s disease and demonstrate an association with cognitive dysfunction. These results provide further evidence to support the involvement of the peripheral nervous system in Parkinson’s disease, previously thought to be a central nervous system disorder.     

Hydrocephalus in 389 patients with aneurysm-associated subarachnoid hemorrhage

Subarachnoid hemorrhage (SAH) often leads to hydrocephalus, which is commonly treated by placement of a ventriculoperitoneal (VP) shunt. There is controversy over which factors affect the need for such treatment. In this study, data were prospectively collected from 389 consecutive patients who presented with an aneurysm-associated SAH at a single center. External ventricular drainage placement was performed as part of the treatment for acute hydrocephalus, and VP shunts were placed in patients with chronic hydrocephalus. The data were retrospectively analyzed using two-sample t-tests, Fisher’s exact test and logistic regression analysis. Overall, shunt dependency occurred in 91 of the 389 patients (23.4%). Using logistic regression analysis, two factors were found to be significantly associated with VP shunt placement: an initial Glasgow Coma Scale (GCS) score of 8–14 (8–14 versus 3–7, p = 0.016; 15 versus 3–7, p = 0.55); and aneurysm coiling (p = 0.017). Patients with an initial GCS score of 8–14 after aneurysm-associated SAH had a 2.5-fold higher risk of receiving a VP shunt than those with a GCS score of 3–7. Those with a GCS of 15 had a 50% lower risk of becoming shunt dependent than did the subgroup with a GCS score of 8–14. To clarify and strengthen these observations, prospective, randomized trials are needed.     

Chronic dietary chlorpyrifos causes long-term spatial memory impairment and thigmotaxic behavior

Little is known about the long-term effects of chronic exposure to low-level organophosphate (OP) pesticides, and the role of neurotransmitter systems, other than the cholinergic system, in mediating OP neurotoxicity. In this study, rats were administered 5 mg/kg/day of chlorpyrifos (CPF) for 6 months commencing at 3-months-of-age. The animals were examined 7 months later (at 16-months-of-age) for spatial learning and memory in the Morris water maze (MWM) and locomotor activity. In addition, we assessed the chronic effects of CPF on glutamatergic and gamma-aminobutyric acid (GABAergic) function using pharmacological challenges with dizocilpine (MK801) and diazepam. Impaired performance related to altered search patterns, including thigmotaxis and long-term spatial memory was noted in the MWM in animals exposed to CPF, pointing to dietary CPF-induced behavioral disturbances, such as anxiety. Twenty-four hours after the 31st session of repeated acquisition task, 0.1 mg/kg MK801, an N-methyl-d-aspartate (NMDA) antagonist was intraperitoneally (i.p.) injected for 4 consecutive days. Decreased latencies in the MWM in the control group were noted after two sessions with MK801 treatment. Once the MWM assessment was completed, animals were administered 0.1 or 0.2 mg/kg of MK801 and 1 or 3 mg/kg of diazepam i.p., and tested for locomotor activity. Both groups, the CPF dietary and control, displayed analogous performance in motor activity. In conclusion, our data point to a connection between the long-term spatial memory, thigmotaxic response and CPF long after the exposure ended.     

Attention,locomotor activity and developmental milestones in rats prenatally exposed to ethanol

RationaleDecline of attentional performance as a function of time engaged on a task and hyperactivity are features shared by children and adults with fetal alcohol syndrome or attentional deficit and hyperactivity disorders.ObjectiveTo investigate the effects of prenatal exposure to two doses of ethanol on developmental milestones, locomotor activity and attention.MethodsWistar rats born from dams exposed to one of four maternal treatments during pregnancy were used: A35 – liquid diet with 35% ethanol-derived calories; A10 – liquid diet with 10% ethanol-derived calories; control – ethanol-free liquid diet; chow – laboratory chow and water.ResultsA35 performed worse in grip strength than control and chow (postnatal day – 14, p < 0.05) but not in negative geotaxis (postnatal days 7–10); A35 also showed more locomotor activity than control and A10 (p < 0.05). Regarding attention, acquisition of the five choice reaction time task was similar between groups, but, the percentage of omission errors from A35 group was greater than other groups at baseline parameters, at shorter (2 s) and longer (7 s) inter-trial intervals and at a shorter stimulus duration (0.5 s) (p < 0.05). The percentage of omissions was larger in A35 as the blocks progressed in sessions with either longer or shorter inter-trial intervals (group × block p < 0.05). Animals from A10 group did not show any impairment in the tasks performed.ConclusionsOur study demonstrates that as well as developmental impairments, prenatal ethanol can produce deficits associated with an increase in attentional demand in rodents, analogous to those observed in fetal alcohol syndrome and attentional deficit and hyperactivity disorders.     

Behavioral disturbances in adult mice following neonatal virus infection or kynurenine treatment – Role of brain kynurenic acid

Exposure to infections in early life is considered a risk-factor for developing schizophrenia. Recently we reported that a neonatal CNS infection with influenza A virus in mice resulted in a transient induction of the brain kynurenine pathway, and subsequent behavioral disturbances in immune-deficient adult mice. The aim of the present study was to investigate a potential role in this regard of kynurenic acid (KYNA), an endogenous antagonist at the glycine site of the N-methyl-d-aspartic acid (NMDA) receptor and at the cholinergic α7 nicotinic receptor. C57BL/6 mice were injected i.p. with neurotropic influenza A/WSN/33 virus (2400 plaque-forming units) at postnatal day (P) 3 or with l-kynurenine (2 × 200 mg/kg/day) at P7–16. In mice neonatally treated with l-kynurenine prepulse inhibition of the acoustic startle, anxiety, and learning and memory were also assessed. Neonatally infected mice showed enhanced sensitivity to d-amphetamine-induced (5 mg/kg i.p.) increase in locomotor activity as adults. Neonatally l-kynurenine treated mice showed enhanced sensitivity to d-amphetamine-induced (5 mg/kg i.p.) increase in locomotor activity as well as mild impairments in prepulse inhibition and memory. Also, d-amphetamine tended to potentiate dopamine release in the striatum in kynurenine-treated mice. These long-lasting behavioral and neurochemical alterations suggest that the kynurenine pathway can link early-life infection with the development of neuropsychiatric disturbances in adulthood.     

Berberine protects against memory impairment and anxiogenic-like behavior in rats submitted to sporadic Alzheimer’s-like dementia: Involvement of acetylcholinesterase and cell death

The present study aimed to investigate the effects of berberine (BRB) on spatial and learning memory, anxiety, acetylcholinesterase activity and cell death in an experimental model of intracerebroventricular streptozotocin (ICV-STZ) induced sporadic Alzheimer’s-like dementia. Sixty male Wistar rats were randomly divided into six groups: control (CTR), BRB 50 mg/kg (BRB 50), BRB 100 mg/kg (BRB 100), streptozotocin (STZ), streptozotocin plus BRB 50 mg/kg (STZ + BRB 50), and streptozotocin plus BRB 100 mg/kg (STZ + BRB 100). Rats were injected with ICV-STZ (3 mg/kg) or saline, and daily oral BRB treatment began on day 4 for a period of 21 days. Behavioral tests were carried out on day 17, and rats were euthanized on day 24. Cell death analysis and determination of acetylcholinesterase activity was performed on the cerebral cortex and hippocampus of the brain. Administration of BRB prevented the memory loss, anxiogenic behavior, increased acetylcholinesterase activity and cell death induced by ICV-STZ. This may be explained, in part, by a protective effect of BRB on ameliorating the progression of neurodegenerative diseases, including Alzheimer’s disease, and the results of this study provide a better understanding of the effect of BRB on the brain. Thus, BRB may act as a potential neuroprotective agent.     

Angiotensin II infusion in man is proinflammatory but has no short-term effects on thrombin generation in vivo

BackgroundAngiotensin (Ang) II may be involved in the development of cardiovascular disease. We examined the potential proinflammatory and prothrombotic effects of Ang II in 16 healthy subjects and in 16 subjects with familial combined hyperlipidemia (FCHL), a condition associated with an increased risk of cardiovascular complications.MethodsWe studied the effects of a three hour intravenous infusion of Ang II (10 ng/kg/min) on plasma concentrations of interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), circulating leukocyte count, tissue plasminogen activator/plasminogen activator inhibitor-1 (t-PA/PAI-1) complexes, prothrombin fragment 1 + 2 (F1 + 2), and thrombin-antithrombin (TAT) complexes. Blood was collected before, during and 1 h after Ang II infusion.ResultsIL-6 was higher in subjects with FCHL at rest (P < 0.05) and increased (P < 0.001) similarly in both groups by Ang II infusion. Also leukocyte count was higher in subjects with FCHL at rest (P < 0.001) and increased (P < 0.001) similarly in both groups by Ang II infusion. T-PA/PAI-1 complexes were higher in subjects with FCHL at rest (P < 0.001) and decreased (P < 0.001) similarly in both groups during Ang II infusion. TNF-α, F1 + 2 and TAT complexes were similar in the two groups at rest and did not change during or after the Ang II infusion.ConclusionsA three hour Ang II infusion increases inflammation and may enhance fibrinolysis but does not affect short term thrombin generation. Subjects with FCHL have signs of increased inflammation and impaired fibrinolysis.     

Permanently compromised NADPH-diaphorase activity within the osmotically activated supraoptic nucleus after in utero but not adult exposure to Aroclor 1254

Stimulated vasopressin (VP) release from magnocellular neuroendocrine cells in the supraoptic nucleus (SON) of hyperosmotic rats is inhibited by treatment with the industrial polychlorinated biphenyl (PCB) mixture, Aroclor 1254. Because VP responses to hyperosmotic stimulation are regulated by nitric oxide (NO) signaling, we studied NO synthase (NOS) activity in the SON of hyperosmotic rats as potential target of PCB-induced disruption of neuroendocrine processes necessary for osmoregulation. To examine PCB-induced changes in NOS activity under normosmotic and hyperosmotic conditions, male Sprague-Dawley rats were exposed to Aroclor 1254 (30 mg/kg/day) in utero and NADPH-diaphorase (NADPH-d) activity was assessed in SON sections at three ages: postnatal day 10, early adult (3–5 months) or late adult (14–16 months). Hyperosmotic treatment increased mean NADPH-d staining density of oil hyperosmotic controls by 19.9% in early adults and 58% in late adulthood vs normosmotic controls. In utero exposure to PCBs reduced hyperosmotic-induced upregulation of NADPH-d activity to control levels in early adults and by 28% in late adults. Basal NADPH-d was reduced in postnatal rats. Rats receiving PCB exposure as early adults orally for 14 days displayed normal responses. Our findings show that developmental but not adult exposure to PCBs significantly reduces NOS responses to hyperosmolality in neuroendocrine cells. Moreover, reduced NADPH-d activity produced by in utero exposure persisted in stimulated late adult rats concomitant with reduced osmoregulatory capacity vs oil controls (375 ± 9 vs 349 ± 5 mOsm/L). These findings suggest that developmental PCBs permanently compromise NOS signaling in the activated neuroendocrine hypothalamus with potential osmoregulatory consequences.     

Positive modulation of α5 GABAA receptors in preadolescence prevents reduced locomotor response to amphetamine in adult female but not male rats prenatally exposed to lipopolysaccharide

We previously demonstrated that lipopolysaccharide (LPS) administered intraperitoneally (i.p.) to pregnant Wistar rat dams, at embryonic days 15 and 16 (E15/16), induced a decrease of baseline locomotor activity and diminished reactivity to amphetamine in adult female offspring. In the present study we aimed to assess the duration of LPS-induced maternal immune activation (MIA) and investigate possible changes in levels of main neurotransmitters in fetal brain during MIA. We hypothesized that the observed behavioral changes may be linked with MIA-induced disturbance of prenatal GABAergic system development, especially with α5 GABA_A receptors (α5GABA_ARs), expression of which takes place between E14 and E17. Thereafter, we set to investigate if later potentiation of α5GABA_ARs in offspring’s preadolescence (from postnatal day 22–28) could prevent the deficit in locomotor reactivity to amphetamine observed in adulthood, at postnatal day P60. The elevation of IL-6 in amniotic fluid 6 h after LPS treatment (100 μg/kg, i.p.) at E15 was concurrent with a significant increase of GABA and decrease of glutamate concentration in fetal brain. Moreover, repeated administration of MP-III-022, a selective positive allosteric modulator of α5GABA_ARs, at a dose (2 mg/kg daily, i.p.) derived from a separate pharmacokinetic study, prevented the LPS-induced decrease in locomotor reactivity to amphetamine (0.5 mg/kg, i.p.) in adult females. These results were not mirrored in the parallel set of experiments with male offspring from LPS-treated rats. The results suggest that pharmacological potentiation of α5GABA_ARs activity in preadolescence may ameliorate at least some of adverse consequences of exposure to MIA in utero.     

Involvement of GABAergic transmission in the midbrain ventral tegmental area in the regulation of hippocampal theta rhythm

Previously we indicated that the ventral tegmental area (VTA) may belong to the system regulating hippocampal theta rhythm. In the present study, we aimed at assessing the role of the GABAergic system of the VTA in regulation of hippocampal electric activity. Male Wistar rats received unilateral intra-VTA microinjection of either bicuculline (50 ng/0.5 μl, n = 9), muscimol (100 ng/0.5 μl, n = 10) or phaclofen (500 ng/0.5 μl, n = 9). 1-min tail pinch stimulations were applied at 10-min intervals to evoke theta rhythm episodes in hippocampus. We analysed peak power (P_max) and corresponding frequency (F_max) of EEG signal at delta and theta bands. Bicuculline induced theta rhythm in both hippocampi with 0 latency, continuous for ca. 33 min. Phaclofen also induced theta but in this group it appeared with latency (17.45 ± 3.16 min on average), lasted for ca. 33.6 min and during this time was interrupted by periods of irregular activity of variable length. Tail pinch was not applied in these groups. Muscimol induced an opposite effect: depression of theta P_max with simultaneous increase in delta P_max and a decrease in F_max delta during episodes of tail pinch-evoked theta. This effect had variable latency and no return to the control EEG could be observed. We propose that GABA activity in the VTA is of tonic character, so that abolition of this mechanism produces immediate effect, i.e. theta induction (strong by GABA_A and weak by GABA_B receptors blockade), whereas enhancing the already present GABAergic inhibition causes delayed, prolonged changes expressed as gradual loss of theta synchronisation.     

A role for orexin in cytotoxic chemotherapy-induced fatigue

Fatigue is the most common symptom related to cytotoxic chemotherapeutic treatment of cancer. Peripheral inflammation associated with cytotoxic chemotherapy is likely a causal factor of fatigue. The neural mechanisms by which cytotoxic chemotherapy associated inflammation induces fatigue behavior are not known. This lack of knowledge hinders development of interventions to reduce or prevent this disabling symptom. Infection induced fatigue/lethargy in rodents is mediated by suppression of hypothalamic orexin activity. Orexin is critical for maintaining wakefulness and motivated behavior. Though there are differences between infection and cytotoxic chemotherapy in some symptoms, both induce peripheral inflammation and fatigue. Based on these similarities we hypothesized that cytotoxic chemotherapy induces fatigue by disrupting orexin neuron activity. We found that a single dose of a cytotoxic chemotherapy cocktail (cyclophosphamide, adriamycin, 5-fluorouracil – CAF) induced fatigue/lethargy in mice and rats as evidenced by a significant decline in voluntary locomotor activity measured by telemetry. CAF induced inflammatory gene expression – IL-1R1 (p < 0.001), IL-6 (p < 0.01), TNFα (p < 0.01), and MCP-1 (p < 0.05) – in the rodent hypothalamus 6–24 h after treatment during maximum fatigue/lethargy. CAF decreased orexin neuron activity as reflected by decreased nuclear cFos localization in orexin neurons 24 h after treatment (p < 0.05) and by decreased orexin-A in cerebrospinal fluid 16 h after treatment (p < 0.001). Most importantly, we found that central administration of1 μg orexin-A restored activity in CAF-treated rats (p < 0.05). These results demonstrate that cytotoxic chemotherapy induces hypothalamic inflammation and that suppression of hypothalamic orexin neuron activity has a causal role in cytotoxic chemotherapy-induced fatigue in rodents.     

Auditory event-related potentials at preschool age in children born very preterm

ObjectiveTo assess auditory event-related potentials at preschool age in children born very preterm (VP, 27.4 ± 1.9 gestational weeks, n = 70) with a high risk of cognitive dysfunction.MethodsWe used an oddball paradigm consisting of a standard tone randomly replaced by one of three infrequent deviants (differing in frequency, sound direction or duration).ResultsThe P1 and N2 latencies were inversely correlated to age (50–63 months) both in VP (r = −0.451, p < 0.001, and r = −0.305, p = 0.01, respectively) and term born controls (TC; n = 15). VP children had smaller P1 than near-term (n = 12) or TC (1.70 ± 0.17 μV vs 2.68 ± 0.41 and 2.92 ± 0.43, respectively; p < 0.05). Mismatch negativity response did not differ between groups.ConclusionsOur data suggest a fast maturation of P1 and N2 responses with fast decrease in P1 and N2 latencies around the age of 5 years. Mismatch negativity response does not seem to be a robust measure for defining abnormalities in VP children.SignificanceIn ERP studies in preschool children, even small, non-significant group differences in age at recording should be corrected for. Very preterm born children at preschool age have aERP patterns as earlier described in full-term born children with cognitive deficits.