Frontal EEG/ERP correlates of attentional processes, cortisol and motivational states in adolescents from lower and higher socioeconomic status

Event-related potentials (ERPs) and other electroencephalographic (EEG) evidence show that frontal brain areas of higher and lower socioeconomic status (SES) children are recruited differently during selective attention tasks. We assessed whether multiple variables related to self-regulation (perceived mental effort) emotional states (e.g., anxiety, stress, etc.) and motivational states (e.g., boredom, engagement, etc.) may co-occur or interact with frontal attentional processing probed in two matched-samples of fourteen lower-SES and higher-SES adolescents. ERP and EEG activation were measured during a task probing selective attention to sequences of tones. Pre- and post-task salivary cortisol and self-reported emotional states were also measured. At similar behavioural performance level, the higher-SES group showed a greater ERP differentiation between attended (relevant) and unattended (irrelevant) tones than the lower-SES group. EEG power analysis revealed a cross-over interaction, specifically, lower-SES adolescents showed significantly higher theta power when ignoring rather than attending to tones, whereas, higher-SES adolescents showed the opposite pattern. Significant theta asymmetry differences were also found at midfrontal electrodes indicating left hypo-activity in lower-SES adolescents. The attended vs. unattended difference in right midfrontal theta increased with individual SES rank, and (independently from SES) with lower cortisol task reactivity and higher boredom. Results suggest lower-SES children used additional compensatory resources to monitor/control response inhibition to distracters, perceiving also more mental effort, as compared to higher-SES counterparts. Nevertheless, stress, boredom and other task-related perceived states were unrelated to SES. Ruling out presumed confounds, this study confirms the midfrontal mechanisms responsible for the SES effects on selective attention reported previously and here reflect genuine cognitive differences.

Electroencephalographic Activity in Response to Procedural Pain in Preterm Infants Born at 28 and 33 Weeks Gestational Age

OBJECTIVES:: Preterm infants undergo frequent painful procedures in the neonatal intensive care unit. Electroencephalography (EEG) changes in reaction to invasive procedures have been reported in preterm and full-term neonates. Frontal EEG asymmetry as an index of emotion during tactile stimulation shows inconsistent findings in full-term infants, and has not been examined in the context of pain in preterm infants. Our aim was to examine whether heel lance for blood collection induces changes in right-left frontal asymmetry, suggesting negative emotional response, in preterm neonates at different gestational age (GA) at birth and different duration of stay in the neonatal intensive care unit. MATERIALS AND METHODS:: Three groups of preterm infants were compared: set 1: group 1 (n=24), born and tested at 28 weeks GA; group 2 (n=22), born at 28 weeks GA and tested at 33 weeks; set 2: group 3 (n=25), born and tested at 33 weeks GA. EEG power was calculated for 30-second artifact-free periods, in standard frequency bandwidths, in 3 phases (baseline, up to 5 min after heel lance, 10 min after heel lance). RESULTS:: No significant differences were found in right-left frontal asymmetry, or in ipsilateral or contralateral somatosensory response, across phases. In contrast, the Behavioral Indicators of Infant Pain scores changed across phase (P

Effect of angiotensin-related antihypertensives on brain neurotransmitter levels in rats.

The extensive clinical experience of angiotensin converting enzyme inhibitors and angiotensin AT(1) receptor antagonists as antihypertensive agents provide numerous examples of anecdotal evidence of improvements in cognition and mood. This study aimed to determine the effect of chronic treatment with the angiotensin converting enzyme inhibitor, perindopril, and the angiotensin AT(1) receptor antagonist, candesartan, on central neurotransmitter levels in the rat. Perindopril (1.0mg/kg/day) or candesartan (10mg/kg/day) was administered via the drinking water at for 1 week, while controls received water alone. At the end of treatment rats were sacrificed, brains removed and discrete regions dissected and analysed for noradrenaline, dopamine and its major metabolites, and serotonin content. As shown previously we found an increase in striatal dopamine levels after perindopril treatment, though this did not extend to the mesolimbic system with neurotransmitter levels unchanged in the hippocampus, nucleus accumbens and frontal cortex. Conversely, candesartan administration produced no change in dopamine, but significant decreases in both DOPAC and HVA in the striatum. In addition chronic candesartan infusion produced a significant increase in the levels of hippocampal noradrenaline and serotonin; and frontal cortex serotonin content. These results demonstrate that while angiotensin converting enzyme inhibitors and angiotensin AT(1) receptor antagonists act as antihypertensives by affecting the renin-angiotensin system, they have divergent actions on brain neurochemistry.

BACE1 mRNA Expression in Alzheimer's Disease Postmortem Brain Tissue

ß-site AßPP cleaving enzyme 1 (BACE1) catalyses the rate-limiting step for production of amyloid-ß (Aß) peptides, involved in the pathological cascade underlying Alzheimer's disease (AD). Elevated BACE1 protein levels and activity have been reported in AD postmortem brains. Our study explored whether this was due to elevated BACE1 mRNA expression. RNA was prepared from five brain regions in three study groups: controls, individuals with AD, and another neurodegenerative disease group affected by either Parkinson's disease (PD) or dementia with Lewy bodies (DLB). BACE1 mRNA levels were measured using quantitative realtime PCR (qPCR) and analyzed by qbasePLUS using validated stably-expressed reference genes. Expression of glial and neuronal markers (glial fibrillary acidic protein (GFAP) and neuron-specific enolase (NSE), respectively) were also analyzed to quantify the changing activities of these cell populations in the tissue. BACE1 mRNA levels were significantly elevated in medial temporal and superior parietal gyri, compared to the PD/DLB and/or control groups. Superior frontal gryus BACE1 mRNA levels were significantly increased in the PD/DLB group, compared to AD and control groups. For the AD group, BACE1 mRNA changes were analyzed in the context of the reduced NSE mRNA, and strongly increased GFAP mRNA levels apparent as AD progressed (indicated by Braak stage). This analysis suggested that increased BACE1 mRNA expression in remaining neuronal cells may contribute to the increased BACE1 protein levels and activity found in brain regions affected by AD.

A voxel based morphometry study investigating brain structural changes in first episode psychosis.

Schizophrenia (SCZ) and bipolar disorder (BP) are associated with neuropathological brain changes, which are believed to disrupt connectivity between brain processes and may have common properties. Patients at first psychotic episode are unique, as one can assess brain alterations at illness inception, when many confounders are reduced or absent. SCZ (N=25) and BP (N=24) patients were recruited in a regional first episode psychosis MRI study. VBM methods were used to study gray matter (GM) and white matter (WM) differences between patient groups and case by case matched controls. For both groups, deficits identified are more discrete than those typically reported in later stages of illness. SCZ patients showed some evidence of GM loss in cortical areas but most notable were in limbic structures such as hippocampus, thalamus and striatum and cerebellum. Consistent with disturbed neural connectivity WM alterations were also observed in limbic structures, the corpus callosum and many subgyral and sublobar regions in the parietal, temporal and frontal lobes. BP patients displayed less evidence of volume changes overall, compared to normal healthy participants, but those changes observed were primarily in WM areas which overlapped with regions identified in SCZ, including thalamus and cerebellum and subgyral and sublobar sites. At first episode of psychosis there is evidence of a neuroanatomical overlap between SCZ and BP with respect to brain structural changes, consistent with disturbed neural connectivity. There are also important differences however in that SCZ displays more extensive structural alteration.

Brain activity during ankle proprioceptive stimulation predicts balance performance in young and older adults

Proprioceptive information from the foot/ankle provides important information regarding body sway for balance control, especially in situations where visual information is degraded or absent. Given known increases in catastrophic injury due to falls with older age, understanding the neural basis of proprioceptive processing for balance control is particularly important for older adults. In the present study, we linked neural activity in response to stimulation of key foot proprioceptors (i.e., muscle spindles) with balance ability across the lifespan. Twenty young and 20 older human adults underwent proprioceptive mapping; foot tendon vibration was compared with vibration of a nearby bone in an fMRI environment to determine regions of the brain that were active in response to muscle spindle stimulation. Several body sway metrics were also calculated for the same participants on an eyes-closed balance task. Based on regression analyses, multiple clusters of voxels were identified showing a significant relationship between muscle spindle stimulation-induced neural activity and maximum center of pressure excursion in the anterior-posterior direction. In this case, increased activation was associated with greater balance performance in parietal, frontal, and insular cortical areas, as well as structures within the basal ganglia. These correlated regions were age- and foot-stimulation side-independent and largely localized to right-sided areas of the brain thought to be involved in monitoring stimulus-driven shifts of attention. These findings support the notion that, beyond fundamental peripheral reflex mechanisms, central processing of proprioceptive signals from the foot is critical for balance control.

Structural brain abnormalities in male schizophrenics reflect fronto-temporal dissociation

Background. Many studies have separately reported abnormalities of frontal and temporal lobe structures in schizophrenia, but little is known of structural fronto-temporal associations in this condition. We investigated whether male patients with chronic schizophrenia would show abnormal patterns of correlation between regional brain volumes.

Methods. Structural magnetic resonance images of the brain in 42 patients were compared with 43 matched unaffected controls. We explored the pattern of association between regional brain volumes by correlational analyses, and non-parametrically tested for significance of between-group differences by randomization.

Results. The schizophrenics demonstrated significant volume deficits in several brain regions (left temporal lobe and hippocampus, right dorsolateral prefrontal cortex), and significant volume increases in the ventricular system (third ventricle and left temporal horn of the lateral ventricle). Controls demonstrated large positive correlations (r > 0.4) between prefrontal and temporal lobe regions. By contrast, inter-regional correlations significantly reduced in schizophrenics included those between prefrontal, anterior cingulate and temporal regions, and between posterior cingulate and hippocampus (P < 0.05). The most salient abnormality in patients was a dissociation between prefrontal and superior temporal gyrus volumes (P < 0.01).

Conclusions. These results support the existence of a relative 'fronto-temporal dissociation' in schizophrenia which we suggest may be due to lack of mutually trophic influences during frontal and temporal lobe development.

Quantitative Measurement of [Na+] and [K+] in Postmortem Human Brain Tissue Indicates Disturbances in Subjects with Alzheimer's Disease and Dementia with Lewy Bodies

Alzheimer’s disease (AD) is associated with significant disturbances in the homeostasis of Na+ and K+ ions as well as reduced levels of Na+/K+ ATPase in the brain. This study used ICP-MS to accurately quantify Na+ and K+ concentrations in human postmortem brain tissue. We analyzed parietal cortex (Brodmann area 7) from 28 cognitively normal age-matched controls, 15 cases of moderate AD, 30 severe AD, and 15 dementia with Lewy bodies (DLB). Associations were investigated between [Na+] and [K+] and a number of variables including diagnosis, age, gender, Braak tangle stage, amyloid-β (Aβ) plaque load, tau load, frontal tissue pH, and APOE genotype. Brains from patients with severe AD had significantly higher (26%; p<0.001) [Na+] (mean 65.43 ± standard error 2.91 mmol/kg) than controls, but the concentration was not significantly altered in moderate AD or DLB. [Na+] correlated positively with Braak stage (r=0.45; p<0.0001), indicating association with disease severity. [K+] in tissue was 10% lower (p<0.05) in moderate AD than controls. However, [K+] in severe AD and DLB (40.97±1.31 mmol/kg) was not significantly different from controls. There was a significant positive correlation between [K+] and Aβ plaque load (r=0.46; p=0.035), and frontal tissue pH (r=0.35; p=0.008). [Na+] was not associated with [K+] across the groups, and neither ion was associated with tau load or APOE genotype. We have demonstrated disturbances of both [Na+] and [K+] in relation to the severity of AD and markers of AD pathology, although it is possible that these relate to late-stage secondary manifestations of the disease pathology.

Metabolic signatures of Huntington's disease (HD): 1H NMR analysis of the polar metabolome in post mortem human brain

Huntington’s disease (HD) is an autosomal neurodegenerative disorder affecting approximately 5-10 persons per 100,000 worldwide. The pathophysiology of HD is not fully understood but the age of onset is known to be highly dependent on the number of CAG triplet repeats in the huntingtin gene. Using 1H NMR spectroscopy this study biochemically profiled 39 brain metabolites in post-mortem striatum (n=14) and frontal lobe (n=14) from HD sufferers and controls (n=28). Striatum metabolites were more perturbed with 15 significantly affected in HD cases, compared with only 4 in frontal lobe (P<0.05; q<0.3). The metabolite which changed most overall was urea which decreased 3.25-fold in striatum (P<0.01). Four metabolites were consistently affected in both brain regions. These included the neurotransmitter precursors tyrosine and L-phenylalanine which were significantly depleted by 1.55-1.58-fold and 1.48-1.54-fold in striatum and frontal lobe, respectively (P=0.02-0.03). They also included L-leucine which was reduced 1.54-1.69-fold (P=0.04-0.09) and myo-inositol which was increased 1.26-1.37-fold (P<0.01). Logistic regression analyses performed with MetaboAnalyst demonstrated that data obtained from striatum produced models which were profoundly more sensitive and specific than those produced from frontal lobe. The brain metabolite changes uncovered in this first 1H NMR investigation of human HD offer new insights into the disease pathophysiology. Further investigations of striatal metabolite disturbances are clearly warranted.

Changes in fos expression in the rat brain after unilateral lesions of the anterior thalamic nuclei

Activity of the immediate early gene c-fos was compared across hemispheres in rats with unilateral anterior thalamic lesions. Fos protein was quantified after rats performed a spatial working memory test in the radial-arm maze, a task that is sensitive to bilateral lesions of the anterior thalamic nuclei. Unilateral anterior thalamic lesions produced evidence of a widespread hippocampal hypoactivity, as there were significant reductions in Fos counts in a range of regions within the ipsilateral hippocampal formation (rostral CA1, rostral dentate gyrus, 'dorsal' hippocampus, presubiculum and postsubiculum). A decrease in Fos levels was also found in the rostral and caudal retrosplenial cortex but not in the parahippocampal cortices or anterior cingulate cortices. The Fos changes seem most closely linked to sites that are also required for successful task performance, supporting the notion that the anterior thalamus, retrosplenial cortex and hippocampus form key components of an interdependent neuronal network involved in spatial mnemonic processing.

Tight junctional abnormality in multiple sclerosis white matter affects all calibres of vessel and is associated with blood-brain barrier leakage and active demyelination

Blood-brain barrier (BBB) hyperpermeability in multiple sclerosis (MS) is associated with lesion pathogenesis and has been linked to pathology in microvascular tight junctions (TJs). This study quantifies the uneven distribution of TJ pathology and its association with BBB leakage. Frozen sections from plaque and normal-appearing white matter (NAWM) in 14 cases were studied together with white matter from six neurological and five normal controls. Using single and double immunofluorescence and confocal microscopy, the TJ-associated protein zonula occludens-1 (ZO-1) was examined across lesion types and tissue categories, and in relation to fibrinogen leakage. Confocal image data sets were analysed for 2198 MS and 1062 control vessels. Significant differences in the incidence of TJ abnormalities were detected between the different lesion types in MS and between MS and control white matter. These were frequent in oil-red O (ORO)+ active plaques, affecting 42% of vessel segments, but less frequent in ORO- inactive plaques (23%), NAWM (13%), and normal (3.7%) and neurological controls (8%). A similar pattern was found irrespective of the vessel size, supporting a causal role for diffusible inflammatory mediators. In both NAWM and inactive lesions, dual labelling showed that vessels with the most TJ abnormality also showed most fibrinogen leakage. This was even more pronounced in active lesions, where 41% of vessels in the highest grade for TJ alteration showed severe leakage. It is concluded that disruption of TJs in MS, affecting both paracellular and transcellular paths, contributes to BBB leakage. TJ abnormality and BBB leakage in inactive lesions suggests either failure of TJ repair or a continuing pathological process. In NAWM, it suggests either pre-lesional change or secondary damage. Clinically inapparent TJ pathology has prognostic implications and should be considered when planning disease-modifying therapy

Differences in expression of junctional adhesion molecule-A and beta catenin in multiple sclerosis brain tissue: increasing evidence for the role of tight junction pathology

Previously we have employed antibodies to the tight junction (TJ)-associated proteins ZO-1 and occludin to describe endothelial tight junction abnormalities, in lesional and normal appearing white matter, in primary and secondary progressive multiple sclerosis (MS). This work is extended here by use of antibodies to the independent TJ-specific proteins and junctional adhesion molecule A & B (JAM-A, JAM-B). We have also assessed the expression in MS of ß-catenin, a protein specific to the TJ-associated adherens junction. Immunocytochemistry and semiquantitative confocal microscopy for JAM-A and ß-catenin was performed on snap-frozen sections from MS cases (n = 11) and controls (n = 6). Data on 1,443 blood vessels was acquired from active lesions (n = 13), inactive lesions (n = 13), NAWM (n = 20) and control white matter (n = 13). In MS abnormal JAM-A expression was found in active (46%) and inactive lesions (21%), comparable to previous data using ZO-1. However, a lower level of TJ abnormality was found in MS NAWM using JAM-A (3%) compared to ZO-1 (13%). JAM-B was strongly expressed on a small number of large blood vessels in control and MS tissues but at too low a level for quantitative analysis. By comparison with the high levels of abnormality observed with the TJ proteins, the adherens junction protein ß-catenin was normally expressed in all MS and control tissue categories. These results confirm, by use of the independent marker JAM-A, that TJ abnormalities are most frequent in active white matter lesions. Altered expression of JAM-A, in addition to affecting junctional tightness may also both reflect and affect leukocyte trafficking, with implications for immune status within the diseased CNS. Conversely, the adherens junction component of the TJ, as indicated by ß-catenin expression is normally expressed in all MS and control tissue categories.