An fMRI study of Joint Attention Experience

Although much is now known about eye movement detection, little is known about the higher cognitive processes involved in joint attention. We developed video stimuli which when watched, engender an experience of joint attention in the observer. This allowed us to compare an experience of joint attention to nonjoint attention within an fMRI scanning environment. Joint attention was associated with activity in the ventromedial frontal cortex, the left superior frontal gyrus (BA10), cingulate cortex, and caudate nuclei. The ventromedial frontal cortex has been consistently shown to be activated during mental state attribution tasks. BA10 may serve a cognitive integration function, which in this case seems to utilize a perception–action matching process. The activation we identified in BA10 overlaps with a location of increased grey matter density that we recently found to be associated with autistic spectrum disorder. This study therefore constitutes evidence that the neural substrate of joint attention also serves a mentalizing function. The developmental failure of this substrate in the left anterior frontal lobe may be important in the etiology of autistic spectrum disorder.

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.

Response variability in Attention Deficit Hyperactivity Disorder: Evidence for neuropsychological heterogeneity

Response time (RT) variability is a common finding in ADHD research. RT variability may reflect frontal cortex function and may be related to deficits in sustained attention. The existence of a sustained attention deficit in ADHD has been debated, largely because of inconsistent evidence of time-on-task effects. A fixed-sequence Sustained Attention to Response Task (SART) was given to 29 control, 39 unimpaired and 24 impaired-ADHD children (impairment defined by the number of commission errors). The response time data were analysed using the Fast Fourier Transform, to define the fast-frequency and slow-frequency contributions to overall response variability. The impaired-ADHD group progressively slowed in RT over the course of the 5.5 min task, as reflected in this group's greater slow-frequency variability. The fast-frequency trial-to-trial variability was also significantly greater, but did not differentially worsen over the course of the task. The higher error rates of the impaired-ADHD group did not become differentially greater over the length of the task. The progressive slowing in mean RT over the course of the task may relate to a deficit in arousal in the impaired-ADHD group. The consistently poor performance in fast-frequency variability and error rates may be due to difficulties in sustained attention that fluctuate on a trial-to-trial basis. (c) 2006 Elsevier Ltd. All rights reserved.

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.

Genetic variation in MME in relation to neprilysin protein and enzyme activity, Aβ levels, and Alzheimer's disease risk

Neprilysin (NEP), also known as membrane metalloendopeptidase (MME), is considered amongst the most important ß-amyloid (Aß)-degrading enzymes with regard to prevention of Alzheimer's disease (AD) pathology. Variation in the NEP gene (MME) has been suggested as a risk factor for AD. We conducted a genetic association study of 7MME SNPs - rs1836914, rs989692, rs9827586, rs6797911, rs61760379, rs3736187, rs701109 - with respect to AD risk in a cohort of 1057 probable and confirmed AD cases and 424 age-matched non-demented controls from the United Kingdom, Italy and Sweden. We also examined the association of these MME SNPs with NEP protein level and enzyme activity, and on biochemical measures of Aß accumulation in frontal cortex - levels of total soluble Aß, oligomeric Aß(1-42), and guanidine-extractable (insoluble) Aß - in a sub-group of AD and control cases with post-mortem brain tissue. On multivariate logistic regression analysis one of the MME variants (rs6797911) was associated with AD risk (P = 0.00052, Odds Ratio (O.R. = 1.40, 95% confidence interval (1.16-1.70)). None of the SNPs had any association with Aß levels; however, rs9827586 was significantly associated with NEP protein level (p=0.014) and enzyme activity (p=0.006). Association was also found between rs701109 and NEP protein level (p=0.026) and a marginally non-significant association was found for rs989692 (p=0.055). These data suggest that MME variation may be associated with AD risk but we have not found evidence that this is mediated through modification of NEP protein level or activity.

Magnetoencephalography reveals slowing of resting peak oscillatory frequency in children born very preterm

Resting cortical activity is characterized by a distinct spectral peak in the alpha frequency range. Slowing of this oscillatory peak toward the upper theta-band has been associated with a variety of neurological and neuropsychiatric conditions and has been attributed to altered thalamocortical dynamics. Children born very preterm exhibit altered development of thalamocortical systems. To test the hypothesis that peak oscillatory frequency is slowed in children born very preterm, we recorded resting magnetoencephalography (MEG) from school age children born very preterm (= 32 wk gestation) without major intellectual or neurological impairment and age-matched full-term controls. Very preterm children exhibit a slowing of peak frequency toward the theta-band over bilateral frontal cortex, together with reduced alpha-band power over bilateral frontal and temporal cortex, suggesting that mildly dysrhythmic thalamocortical interactions may contribute to altered spontaneous cortical activity in children born very preterm.

Altered Long-Range Phase Synchronization and Cortical Activation in Children Born Very Preterm

Children born very preterm, even with broadly normal IQ, commonly show selective difficulties in visuospatial processing and executive functioning. Very little, however, is known what alterations in cortical processing underlie these deficits. We recorded MEG while eight children born very preterm (=32 weeks gestational age) and eight full-term controls performed a visual short-term memory task at mean age 7.5 years (range 6.4 - 8.4). Previously, we demonstrated increased long-range alpha and beta band phase synchronization between MEG sensors during STM retention in a group of 17 full-term children age 6-10 years. Here we present preliminary evidence that long-range phase synchronization in very preterm children, relative to controls, is reduced in the alpha-band but increased in the theta-band. In addition, we investigated cortical activation during STM retention employing synthetic aperture magnetometry (SAM) beamformer to localize changes in gamma-band power. Preliminary results indicate sequential activation of occipital, parietal and frontal cortex in control children, as well as reduced activation in very preterm children relative to controls. These preliminary results suggest that children born very preterm exhibit altered inter-regional functional connectivity and cortical activation during cognitive processing.

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.

The effects of TMS over dorsolateral prefrontal cortex on trans-saccadic memory of multiple objects

Humans typically make several rapid eye movements (saccades) per second. It is thought that visual working memory can retain and spatially integrate three to four objects or features across each saccade but little is known about this neural mechanism. Previously we showed that transcranial magnetic stimulation (TMS) to the posterior parietal cortex and frontal eye fields degrade trans-saccadic memory of multiple object features (Prime, Vesia, & Crawford, 2008, Journal of Neuroscience, 28(27), 6938-6949; Prime, Vesia, & Crawford, 2010, Cerebral Cortex, 20(4), 759-772.). Here, we used a similar protocol to investigate whether dorsolateral prefrontal cortex (DLPFC), an area involved in spatial working memory, is also involved in trans-saccadic memory. Subjects were required to report changes in stimulus orientation with (saccade task) or without (fixation task) an eye movement in the intervening memory interval. We applied single-pulse TMS to left and right DLPFC during the memory delay, timed at three intervals to arrive approximately 100ms before, 100ms after, or at saccade onset. In the fixation task, left DLPFC TMS produced inconsistent results, whereas right DLPFC TMS disrupted performance at all three intervals (significantly for presaccadic TMS). In contrast, in the saccade task, TMS consistently facilitated performance (significantly for left DLPFC/perisaccadic TMS and right DLPFC/postsaccadic TMS) suggesting a dis-inhibition of trans-saccadic processing. These results are consistent with a neural circuit of trans-saccadic memory that overlaps and interacts with, but is partially separate from the circuit for visual working memory during sustained fixation.