NeuRA Imaging Centre

PUBLICATIONS

Characterizing Sexual Behavior in Frontotemporal Dementia.

Ahmed RM, Kaizik C, Irish M, Mioshi E, Dermody N, Kiernan MC, Piguet O, Hodges JR

We aimed to systematically quantify changes in sexual behavior, including current symptoms and changes from prior diagnoses, in behavioral-variant (bvFTD) and semantic dementia (SD), compared to Alzheimer's disease (AD). Overall loss of affection, reduced initiation of sexual activity, and responsiveness is an overwhelming feature of bvFTD. In contrast, aberrant or unusual sexual behavior is observed in the minority of bvFTD patients. The underlying pathophysiology of these changes likely reflects structural and functional changes in frontoinsular and limbic regions including the hypothalamus.

Eating behavior in frontotemporal dementia: Peripheral hormones vs hypothalamic pathology.

Ahmed RM, Latheef S, Bartley L, Irish M, Halliday GM, Kiernan MC, Hodges JR, Piguet O

To contrast the relationships of hormonal eating peptides and hypothalamic volumes to eating behavior and metabolic changes (body mass index [BMI]) in behavioral variant frontotemporal dementia (bvFTD) and semantic variant primary progressive aphasia (svPPA). Eating abnormalities are multifactorial in FTD. In bvFTD, they are in part related to hypothalamic degeneration, with potential disintegration of the network connections between the hypothalamus and orbitofrontal cortex/reward pathways. In svPPA, although hypothalamic volumes are preserved, this group experiences elevated AgRP levels similar to bvFTD, which predicts BMI in both groups. This finding highlights the potential key role of AgRP in eating and metabolic changes and provides a potential target for treatment to modify disease progression.

Comparison of measurements of medial gastrocnemius architectural parameters from ultrasound and diffusion tensor images.

Bolsterlee B, Veeger HE, van der Helm FC, Gandevia SC, Herbert RD

In vivo measurements of muscle architecture provide insight into inter-individual differences in muscle function and could be used to personalise musculoskeletal models. When muscle architecture is measured from ultrasound images, as is frequently done, it is assumed that fascicles are oriented in the image plane and, for some measurements, that the image plane is perpendicular to the aponeurosis at the intersection of fascicle and aponeurosis. This study presents an in vivo validation of these assumptions by comparing ultrasound image plane orientation to three-dimensional reconstructions of muscle fascicles and aponeuroses obtained with diffusion tensor imaging (DTI) and high-resolution anatomical MRI scans. It was found that muscle fascicles were oriented on average at 5.5±4.1° to the ultrasound image plane. On average, ultrasound yielded similar measurements of fascicle lengths to DTI (difference <3mm), suggesting that the measurements were unbiased. The absolute difference in length between any pair of measurements made with ultrasound and DTI was substantial (10mm or 20% of the mean), indicating that the measurements were imprecise. Pennation angles measured with ultrasound were significantly smaller than those measured with DTI (mean difference 6°). This difference was apparent only at the superficial insertion of the muscle fascicles so it was probably due to pressure on the skin applied by the ultrasound probes. It is concluded that ultrasound measurements of deep pennation angles and fascicle lengths in the medial gastrocnemius are unbiased but have a low precision and that superficial pennation angles are underestimated by approximately 10°. The low precision limits the use of ultrasound to personalise fascicle length in musculoskeletal models.

A non-invasive, 3D, dynamic MRI method for measuring muscle moment arms in vivo: demonstration in the human ankle joint and Achilles tendon.

Clarke EC, Martin JH, d'Entremont AG, Pandy MG, Wilson DR, Herbert RD

Muscle moment arms are used widely in biomechanical analyses. Often they are measured in 2D or at a series of static joint positions. In the present study we demonstrate a simple MRI method for measuring muscle moment arms dynamically in 3D from a single range-of-motion cycle. We demonstrate this method in the Achilles tendon for comparison with other methods, and validate the method using a custom apparatus. The method involves registration of high-resolution joint geometry from MRI scans of the stationary joint with low-resolution geometries from ultrafast MRI scans of the slowly moving joint. Tibio-talar helical axes and 3D Achilles tendon moment arms were calculated throughout passive rotation for 10 adult subjects, and compared with recently published data. A simple validation was conducted by comparing MRI measurements with direct physical measurements made on a phantom. The moment arms measured using our method and those of others were similar and there was good agreement between physical measurements (mean 41.0mm) and MRI measurements (mean 39.5mm) made on the phantom. This new method can accurately measure muscle moment arms from a single range-of-motion cycle without the need to control rotation rate or gate the scanning. Supplementary data includes custom software to assist implementation.

Prospective Memory Impairments in Alzheimer's Disease and Behavioral Variant Frontotemporal Dementia: Clinical and Neural Correlates.

Dermody N, Hornberger M, Piguet O, Hodges JR, Irish M

To investigate the clinical and neural correlates of Time- and Event-based PM disruption in AD and the behavioral-variant FTD (bvFTD). Our study reveals the multifaceted nature of PM dysfunction in neurodegenerative disorders, and suggests common and dissociable neurocognitive mechanisms, which subtend these deficits in each patient group. Future studies of PM disturbance in dementia syndromes will be crucial for the development of successful interventions to improve functional independence in the patient's daily life.

Clinical heterogeneity of the C9orf72 genetic mutation in frontotemporal dementia.

Devenney E, Foxe D, Dobson-Stone C, Kwok JB, Kiernan MC, Hodges JR

The C9orf72 genetic mutation represents the most common cause of familial frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). Studies over the last 2 years have revealed a number of key features of this mutation in the fields of clinical neurology, imaging, pathology, and genetics. Despite these efforts, the clinical phenotype appears to extend beyond FTD and ALS into the realm of psychiatric disease, and while highly variable survival rates have been reported, the clinical course of carriers remains relatively unexplored. This report describes two contrasting C9orf72 cases, one with a protracted indolent course dominated by neuropsychiatric features and the other with a rapidly progressive dementia. In both cases, initial structural brain imaging was relatively normal.

Interhemispheric somatosensory differences in chronic pain reflect abnormality of the healthy side.

Di Pietro F, Stanton TR, Moseley GL, Lotze M, McAuley JH

It is widely accepted that complex regional pain syndrome (CRPS) is associated with shrinkage of the primary somatosensory cortex (S1) representation of the affected limb. However, supporting evidence is surprisingly limited and may be compromised by high risk of bias. This study compared the S1 spatial representation of the hand in 17 patients with upper-limb CRPS to 16 healthy controls, using functional MRI. Innocuous vibration was delivered to digits one (D1) and five (D5) in a block-design. Resultant activation maxima were located within a bilateral S1 mask, determined a priori. Distance between D1 and D5 activation maxima, calculated for both hands, was used as a measure of S1 representation. Analyses were blinded to group and hand. In patients, S1 representation was smaller for the affected hand than it was for the healthy hand (t(11) = 2.02, P = 0.03), as predicted. However, S1 representation of the affected hand was no different to that of either hand in controls. Critically, S1 representation of the healthy hand of patients was larger than that of controls' hands. CRPS seems to be associated with an enlarged representation of the healthy hand, not a smaller representation of the affected hand. These findings raise important questions about neuroplasticity in CRPS.

Reversal of functional changes in the brain associated with obstructive sleep apnoea following 6 months of CPAP.

Fatouleh RH, Lundblad LC, Macey PM, McKenzie DK, Henderson LA, Macefield VG

Obstructive sleep apnoea (OSA) is associated with an increase in the number of bursts of muscle sympathetic nerve activity (MSNA), leading to neurogenic hypertension. Continuous positive airway pressure (CPAP) is the most effective and widely used treatment for preventing collapse of the upper airway in OSA. In addition to improving sleep, CPAP decreases daytime MSNA towards control levels. It remains unknown how this restoration of MSNA occurs, in particular whether CPAP treatment results in a simple readjustment in activity of those brain regions responsible for the initial increase in MSNA or whether other brain regions are recruited to over-ride aberrant brain activity. By recording MSNA concurrently with functional Magnetic Resonance Imaging (fMRI), we aimed to assess brain activity associated with each individual subject's patterns of MSNA prior to and following 6 months of CPAP treatment. Spontaneous fluctuations in MSNA were recorded via tungsten microelectrodes inserted into the common peroneal nerve in 13 newly diagnosed patients with OSA before and after 6 months of treatment with CPAP and in 15 healthy control subjects while lying in a 3 T MRI scanner. Blood Oxygen Level Dependent (BOLD) contrast gradient echo, echo-planar images were continuously collected in a 4 s ON, 4 s OFF (200 volumes) sampling protocol. MSNA was significantly elevated in newly diagnosed OSA patients compared to control subjects (55 ± 4 vs 26 ± 2 bursts/min). Fluctuations in BOLD signal intensity in multiple regions covaried with the intensity of the concurrently recorded bursts of MSNA. There was a significant fall in MSNA after 6 months of CPAP (39 ± 2 bursts/min). The reduction in resting MSNA was coupled with significant falls in signal intensity in precuneus bilaterally, the left and right insula, right medial prefrontal cortex, right anterior cingulate cortex, right parahippocampus and the left and right retrosplenial cortices. These data support our contention that functional changes in these suprabulbar sites are, via projections to the brainstem, driving the augmented sympathetic outflow to the muscle vascular bed in untreated OSA.

Neurophysiological correlates of dysregulated emotional arousal in severe traumatic brain injury.

Fisher AC, Rushby JA, McDonald S, Parks N, Piguet O

This study aimed to elucidate relationships between dysregulated emotional arousal after severe traumatic brain injury (TBI), alpha power and skin conductance levels (SCL), and brain atrophy. Findings suggest that alpha power provides a sensitive measure of dysregulated emotional arousal post-TBI. Atrophy in pertinent brain structures may contribute to these disturbances.

MR Elastography Can Be Used to Measure Brain Stiffness Changes as a Result of Altered Cranial Venous Drainage During Jugular Compression.

Hatt A, Cheng S, Tan K, Sinkus R, Bilston LE

Jugular compression influences cerebral CSF hydrodynamics in healthy subjects and can increase brain tissue stiffness, but the magnitude of the stiffening depends on the percentage of cranial blood draining through the internal jugular veins during compression—that is, subjects who maintain venous drainage through the internal jugular veins during jugular compression have stiffer brains than those who divert venous blood through alternative pathways. These methods may be useful for studying this phenomenon in patients with the syndrome of inappropriately low-pressure acute hydrocephalus and other conditions.

Changes in the length and three-dimensional orientation of muscle fascicles and aponeuroses with passive length changes in human gastrocnemius muscles.

Herbert RD, Héroux ME, Diong J, Bilston LE, Gandevia SC, Lichtwark GA

The mechanisms by which skeletal muscles lengthen and shorten are potentially complex. When the relaxed human gastrocnemius muscle is at its shortest in vivo lengths it falls slack (i.e. it does not exert any passive tension). It has been hypothesised that when the muscle is passively lengthened, slack is progressively taken up, first in some muscle fascicles then in others. Two-dimensional imaging methods suggest that, once the slack is taken up, changes in muscle length are mediated primarily by changes in the lengths of the tendinous components of the muscle. The aims of this study were to test the hypothesis that there is progressive engagement of relaxed muscle fascicles, and to quantify changes in the length and three-dimensional orientation of muscle fascicles and tendinous structures during passive changes in muscle length. Ultrasound imaging was used to determine the location, in an ultrasound image plane, of the proximal and distal ends of muscle fascicles at 14 sites in the human gastrocnemius muscle as the ankle was rotated passively through its full range. A three-dimensional motion analysis system recorded the location and orientation of the ultrasound image plane and the leg. These data were used to generate dynamic three-dimensional reconstructions of the architecture of the muscle fascicles and aponeuroses. There was considerable variability in the measured muscle lengths at which the slack was taken up in individual muscle fascicles. However, that variability was not much greater than the error associated with the measurement procedure. An analysis of these data which took into account the possible correlations between errors showed that, contrary to our earlier hypothesis, muscle fascicles are not progressively engaged during passive lengthening of the human gastrocnemius. Instead, the slack is taken up nearly simultaneously in all muscle fascicles. Once the muscle is lengthened sufficiently to take up the slack, about half of the subsequent increase in muscle length is due to elongation of the tendinous structures and half is due to elongation of muscle fascicles, at least over the range of muscle-tendon lengths that was investigated (up to ∼60 or 70% of the range of in vivo lengths). Changes in the alignment of muscle fascicles and flattening of aponeuroses contribute little to the total change in muscle length.

The Evolution of Caregiver Burden in Frontotemporal Dementia with and without Amyotrophic Lateral Sclerosis.

Hsieh S, Leyton CE, Caga J, Flanagan E, Kaizik C, O'Connor CM, Kiernan MC, Hodges JR, Piguet O, Mioshi E

The trajectory of perceived burden differs across the FTD-ALS spectrum, with SD and ALSFTD caregivers demonstrating an increased burden that develops over time, compared to a persistently high level for bvFTD caregivers, evident throughout the disease course. The evolution of burden in these three syndromes likely reflects the initial presentation and clinical characterization that develops with time. Psycho-education programs for caregivers, which provide better coping strategies for challenging behaviors, may reduce levels of burden experienced with disease progression.

Scene construction impairments in Alzheimer's disease - A unique role for the posterior cingulate cortex.

Irish M, Halena S, Kamminga J, Tu S, Hornberger M, Hodges JR

Episodic memory dysfunction represents one of the most prominent and characteristic clinical features of patients with Alzheimer's disease (AD), attributable to the degeneration of medial temporal and posterior parietal regions of the brain. Recent studies have demonstrated marked impairments in the ability to envisage personally relevant events in the future in AD. It remains unclear, however, whether AD patients can imagine fictitious scenes free from temporal constraints, a process that is proposed to rely fundamentally upon the integrity of the hippocampus. The objective of the present study was to investigate the capacity for atemporal scene construction, and its associated neural substrates, in AD. Fourteen AD patients were tested on the scene construction task and their performance was contrasted with 14 age- and education-matched healthy older Control participants. Scene construction performance was strikingly compromised in the AD group, with significant impairments evident for provision of contextual details, spatial coherence, and the overall richness of the imagined experience. Voxel-based morphometry analyses based on structural MRI revealed significant associations between scene construction capacity and atrophy in posterior parietal and lateral temporal brain structures in AD. In contrast, scene construction performance in Controls was related to integrity of frontal, parietal, and medial temporal structures, including the parahippocampal gyrus and posterior hippocampus. The posterior cingulate cortex (PCC) emerged as the common region implicated for scene construction performance across participant groups. Our study highlights the importance of regions specialised for spatial and contextual processing for the construction of atemporal scenes. Damage to these regions in AD compromises the ability to construct novel scenes, leading to the recapitulation of content from previously experienced events.

'Language of the past' - Exploring past tense disruption during autobiographical narration in neurodegenerative disorders.

Irish M, Kamminga J, Addis DR, Crain S, Thornton R, Hodges JR, Piguet O

Compromised retrieval of autobiographical memory (ABM) is well established in neurodegenerative disorders. The recounting of autobiographical events is inextricably linked to linguistic knowledge, yet no study to date has investigated whether tense use during autobiographical narration is disrupted in dementia syndromes. This study investigated the incidence of correct past tense use during ABM narration in patients with Alzheimer's disease (AD, n = 10) and semantic dementia (SD, n = 10) in comparison with healthy older Controls (n = 10). Autobiographical narratives were analysed for episodic content (internal/external) and classified according to tense use (past/present). Across both patient groups, use of the past tense was significantly compromised relative to Controls, with increased levels of off-target present tense verbs observed. Voxel-based morphometry analyses based on structural MRI revealed differential associations between past tense use and regions of grey matter intensity in the brain. Bilateral temporal cortices were implicated in the SD group, whereas frontal, lateral, and medial temporal regions including the right hippocampus emerged in AD. This preliminary study provides the first demonstration of the disruption of specific linguistic constructs during autobiographical narration in AD and SD. Future studies are warranted to clarify at what point in the disease trajectory such deficits in tense use emerge, and whether these deficits are a product or contributing factor in memory disruption in these syndromes.

Differentiating between right-lateralised semantic dementia and behavioural-variant frontotemporal dementia: an examination of clinical characteristics and emotion processing.

Kamminga J, Kumfor F, Burrell JR, Piguet O, Hodges JR, Irish M

This study demonstrates comparable deficits in facial emotion processing in right SD and bvFTD, in keeping with their similar clinical profiles. These deficits are attributable to divergent neural substrates in each patient group, namely, right lateralised regions in right SD, versus predominantly left lateralised regions in bvFTD.

Selective Estrogen Receptor Modulation Increases Hippocampal Activity during Probabilistic Association Learning in Schizophrenia.

Kindler J, Weickert CS, Skilleter AJ, Catts SV, Lenroot R, Weickert TW

People with schizophrenia show probabilistic association learning impairment in conjunction with abnormal neural activity. The selective estrogen receptor modulator (SERM) raloxifene preserves neural activity during memory in healthy older men and improves memory in schizophrenia. Here, we tested the extent to which raloxifene modifies neural activity during learning in schizophrenia. Nineteen people with schizophrenia participated in a twelve-week randomized, double-blind, placebo-controlled, cross-over adjunctive treatment trial of the SERM raloxifene administered orally at 120 mg daily to assess brain activity during probabilistic association learning using functional magnetic resonance imaging (fMRI). Raloxifene improved probabilistic association learning and significantly increased fMRI BOLD activity in the hippocampus and parahippocampal gyrus relative to placebo. A separate region of interest confirmatory analysis in 21 patients vs 36 healthy controls showed a positive association between parahippocampal neural activity and learning in patients, but no such relationship in the parahippocampal gyrus of healthy controls. Thus, selective estrogen receptor modulation by raloxifene concurrently increases activity in the parahippocampal gyrus and improves probabilistic association learning in schizophrenia. These results support a role for estrogen receptor modulation of mesial temporal lobe neural activity in the remediation of learning disabilities in both men and women with schizophrenia.

Bridging Three Orders of Magnitude: Multiple Scattered Waves Sense Fractal Microscopic Structures via Dispersion.

Lambert SA, Näsholm SP, Nordsletten D, Michler C, Juge L, Serfaty JM, Bilston L, Guzina B, Holm S, Sinkus R

Wave scattering provides profound insight into the structure of matter. Typically, the ability to sense microstructure is determined by the ratio of scatterer size to probing wavelength. Here, we address the question of whether macroscopic waves can report back the presence and distribution of microscopic scatterers despite several orders of magnitude difference in scale between wavelength and scatterer size. In our analysis, monosized hard scatterers 5  μm in radius are immersed in lossless gelatin phantoms to investigate the effect of multiple reflections on the propagation of shear waves with millimeter wavelength. Steady-state monochromatic waves are imaged in situ via magnetic resonance imaging, enabling quantification of the phase velocity at a voxel size big enough to contain thousands of individual scatterers, but small enough to resolve the wavelength. We show in theory, experiments, and simulations that the resulting coherent superposition of multiple reflections gives rise to power-law dispersion at the macroscopic scale if the scatterer distribution exhibits apparent fractality over an effective length scale that is comparable to the probing wavelength. Since apparent fractality is naturally present in any random medium, microstructure can thereby leave its fingerprint on the macroscopically quantifiable power-law exponent. Our results are generic to wave phenomena and carry great potential for sensing microstructure that exhibits intrinsic fractality, such as, for instance, vasculature.

Semantic deficits in amyotrophic lateral sclerosis.

Leslie FV, Hsieh S, Caga J, Savage SA, Mioshi E, Hornberger M, Kiernan MC, Hodges JR, Burrell JR

Our objective was to investigate, and establish neuroanatomical correlates of, semantic deficits in amyotrophic lateral sclerosis (ALS) and amyotrophic lateral sclerosis-frontotemporal dementia (ALS-FTD), compared to semantic dementia (SD) and controls. Semantic deficits were evaluated using a naming and semantic knowledge composite score, comprising verbal and non-verbal neuropsychological measures of single-word processing (confrontational naming, comprehension, and semantic association) from the Sydney Language Battery (SYDBAT) and Addenbrooke's Cognitive Examination – Revised (ACE-R). Voxel based morphometry (VBM) analysis was conducted using the region of interest approach. In total, 84 participants were recruited from a multidisciplinary research clinic in Sydney. Participants included 17 patients with ALS, 19 with ALS-FTD, 22 with SD and 26 age- and education-matched healthy controls. Significant semantic deficits were observed in ALS and ALS-FTD compared to controls. The severity of semantic deficits varied across the clinical phenotypes: ALS patients were less impaired than ALS-FTD patients, who in turn were not as impaired as SD patients. Anterior temporal lobe atrophy significantly correlated with semantic deficits. In conclusion, semantic impairment is a feature of ALS and ALS-FTD, and reflects the severity of temporal lobe pathology.

Is the logopenic-variant of primary progressive aphasia a unitary disorder?

Leyton CE, Hodges JR, McLean CA, Kril JJ, Piguet O, Ballard KJ

Logopenic progressive aphasia is one of the clinical presentations of primary progressive aphasia and formally defined by the co-occurrence of impaired naming and sentence repetition. Impaired naming is attributed to failure of lexical retrieval, which is a multi-staged process subserved by anatomically segregated brain regions. By dissecting the neurocognitive processes involved in impaired naming, we aimed to disentangle the clinical and neuroanatomical heterogeneity of this syndrome. Twenty-one individuals (66.7% females, age range 53-83 years) who fulfilled diagnostic criteria for logopenic variant and had at least two clinical and language assessments, 1 year apart, were recruited and matched for age, sex distribution and level of education with a healthy control sample (n = 18). All participants underwent a structural brain scan at the first visit and surface-wise statistical analysis using Freesurfer. Seventeen participants with logopenic variant underwent amyloid imaging, with 14 demonstrating high amyloid retention. Based on their performance on single-word comprehension, repetition and confrontation naming, three subgroups of logopenic cases with distinctive linguistic profiles and distribution of atrophy were identified. The first subgroup (n = 10) demonstrated pure anomia and left-sided atrophy in the posterior inferior parietal lobule and lateral temporal cortex. The second subgroup (n = 6), presented additional mild deficits in single-word comprehension, and also exhibited bilateral thinning of the fusiform gyri. The third subgroup (n = 5) showed additional impaired single-word repetition, and cortical thinning focused on the left superior temporal gyrus. The subgroups differed in the proportion of cases with high amyloid retention and in the rate of decline of naming performance over time, suggesting that neurodegeneration spreads differentially throughout regions subserving word processing. In line with previous reports, these results confirm the extensive damage to the language network and, in part, explain the clinical heterogeneity observed across logopenic cases.

Alterations of GABA and glutamate-glutamine levels in premenstrual dysphoric disorder: a 3T proton magnetic resonance spectroscopy study.

Liu B, Wang G, Gao D, Gao F, Zhao B, Qiao M, Yang H, Yu Y, Ren F, Yang P, Chen W, Rae CD

Increasing evidence has suggested that the GABAergic neurotransmitter system is involved in the pathogenesis of premenstrual dysphoric disorder (PMDD). We used proton magnetic resonance spectroscopy ((1)H MRS) to investigate whether PMDD is associated with alterations in brain GABA levels. Levels of glutamate-glutamine (Glx) were also explored. Participants comprised 22 women with PMDD and 22 age-matched healthy controls who underwent 3T (1)H MRS during the late luteal phase of the menstrual cycle. GABA+ and Glx levels were quantified in the anterior cingulate cortex/medial prefrontal cortex (ACC/mPFC) and the left basal ganglia (ltBG). Water-scaled GABA+ concentrations and GABA+/tCr ratios were significantly lower in both the ACC/mPFC and ltBG regions of PMDD women than in healthy controls. Glx/tCr ratios were significantly higher in the ACC/mPFC region of PMDD women than healthy controls. Our preliminary findings provide the first report of abnormal levels of GABA+ and Glx in mood-related brain regions of women with PMDD, indicating that dysregulation of the amino acid neurotransmitter system may be an important neurobiological mechanism in the pathogenesis of PMDD.

Brain stem activity changes associated with restored sympathetic drive following CPAP treatment in OSA subjects: a longitudinal investigation.

Lundblad LC, Fatouleh RH, McKenzie DK, Macefield VG, Henderson LA

Obstructive sleep apnea (OSA) is associated with significantly elevated muscle sympathetic nerve activity (MSNA), leading to hypertension and increased cardiovascular morbidity. Although little is known about the mechanisms responsible for the sympathoexcitation, we have recently shown that the elevated MSNA in OSA is associated with altered neural processing in various brain stem sites, including the dorsolateral pons, rostral ventrolateral medulla, medullary raphe, and midbrain. Given the risk associated with elevated MSNA, we aimed to determine if treatment of OSA with continuous positive airway pressure (CPAP) would reduce the elevated MSNA and reverse the brain stem functional changes associated with the elevated MSNA. We performed concurrent recordings of MSNA and blood oxygen level-dependent (BOLD) signal intensity of the brain stem, using high-resolution functional magnetic resonance imaging, in 15 controls and 13 subjects with OSA, before and after 6 mo CPAP treatment. As expected, 6 mo of CPAP treatment significantly reduced MSNA in subjects with OSA, from 54 ± 4 to 23 ± 3 bursts/min and from 77 ± 7 to 36 ± 3 bursts/100 heart beats. Importantly, we found that MSNA-coupled changes in BOLD signal intensity within the dorsolateral pons, medullary raphe, and rostral ventrolateral medulla returned to control levels. That is, CPAP treatment completely reversed brain stem functional changes associated with elevated MSNA in untreated OSA subjects. These data highlight the effectiveness of CPAP treatment in reducing one of the most significant health issues associated with OSA, that is, elevated MSNA and its associated elevated morbidity.

Autonomic responses to exercise: cortical and subcortical responses during post-exercise ischaemia and muscle pain.

Macefield VG, Henderson LA

Sustained isometric contraction of skeletal muscle causes an increase in blood pressure, due to an increase in cardiac output and an increase in total peripheral resistance-brought about by an increase in sympathetically-mediated vasoconstriction. Both central command and reflex inputs from metaboreceptors in the contracting muscles have been shown to contribute to this sympathetically mediated increase in blood pressure. Occluding the blood supply and trapping the metabolites in the contracted muscle (post-exercise ischaemia) has shown that, while heart rate returns to baseline following exercise, the increase in MSNA and blood pressure persists in the absence of central command-sustained by peripheral inputs. Post-exercise ischaemia activates group III and IV muscle afferents, which are also activated during noxious stimulation. Indeed, post-exercise ischaemia is painful, so what is the role of pain in the increase in blood pressure? Intramuscular injection of hypertonic saline causes a deep dull ache, not unlike that produced by post-exercise ischaemia, and we have shown that this can cause a sustained increase in MSNA and blood pressure. We have used functional Magnetic Resonance Imaging (fMRI) of the brain to identify the cortical and subcortical sites involved in the sensory processing of muscle pain, and in the generation of the autonomic responses to muscle pain, produced either by post-exercise ischaemia or intramuscular injection of hypertonic saline. During static hand-grip exercise there were parallel increases in signal intensity in the contralateral primary motor cortex, deep cerebellar nuclei and cerebellar cortex that ceased at the end of the exercise, reflecting the start and end of central command. Progressive increases during the contraction phase occurred in the contralateral insula, as well as the contralateral primary somatosensory cortex, and continued during the period of post-exercise ischaemia. Decreases in signal intensity occurred in the perigenual anterior cingulate cortex during the contraction phase; these too were sustained during post-exercise ischaemia. That similar changes occurred with intramuscular injection of hypertonic saline suggests that much of the cortical and subcortical changes seen during post-exercise ischaemia reflect the sensory and affective attributes of the muscle pain, rather than in furnishing the cardiovascular responses per se.

A new role for α-ketoglutarate dehydrogenase complex: regulating metabolism through post-translational modification of other enzymes.

McKenna MC, Rae CD

This Editorial highlights a study by Gibson et al. published in this issue of JNeurochem, in which the authors reveal a novel role for the α-ketoglutarate dehydrogenase complex (KGDHC) in post-translational modification of proteins. KGDHC may catalyze post-translational modification of itself as well as several other proteins by succinylation of lysine residues. The authors' report of an enzyme responsible for succinylation of key mitochondrial enzymes represents a major step toward our understanding of the complex functional metabolome. TCA, tricarboxylic acid; KG, α-ketoglutarate; KGDHC, α-ketoglutarate dehydrogenase complex; FUM, fumarase; MDH, malate dehydrogenase; ME, malic enzyme; GDH, glutamate dehydrogenase; AAT, aspartate aminotransferase; GS, glutamine synthetase; PAG, phosphate-activated glutaminase; SIRT3, silent information regulator 3; SIRT5, silent information regulator 5.

Testosterone and reward prediction-errors in healthy men and men with schizophrenia.

Morris RW, Purves-Tyson TD, Weickert CS, Rothmond D, Lenroot R, Weickert TW

Sex hormones impact reward processing, which is dysfunctional in schizophrenia; however, the degree to which testosterone levels relate to reward-related brain activity in healthy men and the extent to which this relationship may be altered in men with schizophrenia has not been determined. We used functional magnetic resonance imaging (fMRI) to measure neural responses in the striatum during reward prediction-errors and hormone assays to measure testosterone and prolactin in serum. To determine if testosterone can have a direct effect on dopamine neurons, we also localized and measured androgen receptors in human midbrain with immunohistochemistry and quantitative PCR. We found correlations between testosterone and prediction-error related activity in the ventral striatum of healthy men, but not in men with schizophrenia, such that testosterone increased the size of positive and negative prediction-error related activity in a valence-specific manner. We also identified midbrain dopamine neurons that were androgen receptor immunoreactive, and found that androgen receptor (AR) mRNA was positively correlated with tyrosine hydroxylase (TH) mRNA in human male substantia nigra. The results suggest that sex steroid receptors can potentially influence midbrain dopamine biosynthesis, and higher levels of serum testosterone are linked to better discrimination of motivationally-relevant signals in the ventral striatum, putatively by modulation of the dopamine biosynthesis pathway via AR ligand binding. However, the normal relationship between serum testosterone and ventral striatum activity during reward learning appears to be disrupted in schizophrenia.

Altered resting-state network connectivity in stroke patients with and without apraxia of speech.

New AB, Robin DA, Parkinson AL, Duffy JR, McNeil MR, Piguet O, Hornberger M, Price CJ, Eickhoff SB, Ballard KJ

Motor speech disorders, including apraxia of speech (AOS), account for over 50% of the communication disorders following stroke. Given its prevalence and impact, and the need to understand its neural mechanisms, we used resting state functional MRI to examine functional connectivity within a network of regions previously hypothesized as being associated with AOS (bilateral anterior insula (aINS), inferior frontal gyrus (IFG), and ventral premotor cortex (PM)) in a group of 32 left hemisphere stroke patients and 18 healthy, age-matched controls. Two expert clinicians rated severity of AOS, dysarthria and nonverbal oral apraxia of the patients. Fifteen individuals were categorized as AOS and 17 were AOS-absent. Comparison of connectivity in patients with and without AOS demonstrated that AOS patients had reduced connectivity between bilateral PM, and this reduction correlated with the severity of AOS impairment. In addition, AOS patients had negative connectivity between the left PM and right aINS and this effect decreased with increasing severity of non-verbal oral apraxia. These results highlight left PM involvement in AOS, begin to differentiate its neural mechanisms from those of other motor impairments following stroke, and help inform us of the neural mechanisms driving differences in speech motor planning and programming impairment following stroke.

Memory and emotion processing performance contributes to the diagnosis of non-semantic primary progressive aphasia syndromes.

Piguet O, Leyton CE, Gleeson LD, Hoon C, Hodges JR

To improve diagnostic accuracy of nfv-PPA and lv-PPA using tasks measuring non-language cognition and emotion processing. Non-language presenting features can help differentiate between the two non-semantic PPA syndromes, with a double dissociation observed on tasks of episodic memory and emotion processing. Based on performance on these tasks, we propose a decision tree as a complementary method to differentiate between the two non-semantic variants. These findings have important clinical implications, with identification of patients who may potentially benefit existing therapeutic interventions currently available for Alzheimer's disease.

Association of serum VEGF levels with prefrontal cortex volume in schizophrenia.

Pillai A, Howell KR, Ahmed AO, Weinberg D, Allen KM, Bruggemann J, Lenroot R, Liu D, Galletly C, Weickert CS, Weickert TW

A large body of evidence indicates alterations in brain regional cellular energy metabolism and blood flow in schizophrenia. Among the different molecules regulating blood flow, vascular endothelial growth factor (VEGF) is generally accepted as the major factor involved in the process of angiogenesis. In the present study, we examined whether peripheral VEGF levels correlate with changes in the prefrontal cortex (PFC) volume in patients with schizophrenia and in healthy controls. Whole-blood samples were obtained from 96 people with schizophrenia or schizoaffective disorder and 83 healthy controls. Serum VEGF protein levels were analyzed by enzyme-linked immunosorbent assay, whereas quantitative PCR was performed to measure interleukin-6 (IL-6, a pro-inflammatory marker implicated in schizophrenia) mRNA levels in the blood samples. Structural magnetic resonance imaging scans were obtained using a 3T Achieva scanner on a subset of 59 people with schizophrenia or schizoaffective disorder and 65 healthy controls, and prefrontal volumes were obtained using FreeSurfer software. As compared with healthy controls, individuals with schizophrenia had a significant increase in log-transformed mean serum VEGF levels (t(177)=2.9, P=0.005). A significant inverse correlation (r=-0.40, P=0.002) between serum VEGF and total frontal pole volume was found in patients with schizophrenia/schizoaffective disorder. Moreover, we observed a significant positive association (r=0.24, P=0.03) between serum VEGF and IL-6 mRNA levels in patients with schizophrenia. These findings suggest an association between serum VEGF and inflammation, and that serum VEGF levels are related to structural abnormalities in the PFC of people with schizophrenia.

The Relationship Between Plasma Aβ Levels, Cognitive Function and Brain Volumetrics: Sydney Memory and Ageing Study.

Poljak A, Crawford JD, Smythe GA, Brodaty H, Slavin MJ, Kochan NA, Trollor JN, Wen W, Mather KA, Assareh AA, Ng PC, Sachdev PS

Determine whether (1) a relationship exists between plasma amyloid-β (Aβ)1- 40 and 1-42 peptide levels, brain volumetrics and cognitive performance in elderly individuals with and without amnestic mild cognitive impairment (aMCI), (2) plasma Aβ peptide levels differ between apolipoprotein E (APOE) ε4 carriers and non-carriers and (3) longitudinal changes in cognition and brain volume relate to Aβ levels. Plasma Aβ levels and the Aβ1-42/1-40 ratio are related to cognition and hippocampal volumes, with differential associations of Aβ1-40 and Aβ1-42 in ε4 carriers and non-carriers. These data support the Aβ sink model of AD pathology, and suggest that plasma Aβ measures may serve as biomarkers of AD.

Metabolomic Approaches to Defining the Role(s) of GABAρ Receptors in the Brain.

Rae C, Nasrallah FA, Balcar VJ, Rowlands BD, Johnston GA, Hanrahan JR

The inhibitory neurotransmitter γ-aminobutyric acid (GABA) acts through various types of receptors in the central nervous system. GABAρ receptors, defined by their characteristic pharmacology and presence of ρ subunits in the channel structure, are poorly understood and their role in the cortex is ill-defined. Here, we used a targeted pharmacological, NMR-based functional metabolomic approach in Guinea pig brain cortical tissue slices to identify a distinct role for these receptors. We compared metabolic fingerprints generated by a range of ligands active at GABAρ and included these in a principal components analysis with a library of other metabolic fingerprints obtained using ligands active at GABAA and GABAB, with inhibitors of GABA uptake and with compounds acting to inhibit enzymes active in the GABAergic system. This enabled us to generate a metabolic "footprint" of the GABAergic system which revealed classes of metabolic activity associated with GABAρ which are distinct from other GABA receptors. Antagonised GABAρ produce large metabolic effects at extrasynaptic sites suggesting they may be involved in tonic inhibition.

Creatine as a booster for human brain function. How might it work?

Rae CD, Bröer S

Creatine, a naturally occurring nitrogenous organic acid found in animal tissues, has been found to play key roles in the brain including buffering energy supply, improving mitochondrial efficiency, directly acting as an anti-oxidant and acting as a neuroprotectant. Much of the evidence for these roles has been established in vitro or in pre-clinical studies. Here, we examine the roles of creatine and explore the current status of translation of this research into use in humans and the clinic. Some further possibilities for use of creatine in humans are also discussed.

Silent information regulator 1 modulator resveratrol increases brain lactate production and inhibits mitochondrial metabolism, whereas SRT1720 increases oxidative metabolism.

Rowlands BD, Lau CL, Ryall JG, Thomas DS, Klugmann M, Beart PM, Rae CD

Silent information regulators (SIRTs) have been shown to deacetylate a range of metabolic enzymes, including those in glycolysis and the Krebs cycle, and thus alter their activity. SIRTs require NAD(+) for their activity, linking cellular energy status to enzyme activity. To examine the impact of SIRT1 modulation on oxidative metabolism, this study tests the effect of ligands that are either SIRT-activating compounds (resveratrol and SRT1720) or SIRT inhibitors (EX527) on the metabolism of (13)C-enriched substrates by guinea pig brain cortical tissue slices with (13)C and (1)H nuclear magnetic resonance spectroscopy. Resveratrol increased lactate labeling but decreased incorporation of (13)C into Krebs cycle intermediates, consistent with effects on AMPK and inhibition of the F0/F1-ATPase. By testing with resveratrol that was directly applied to astrocytes with a Seahorse analyzer, increased glycolytic shift and increased mitochondrial proton leak resulting from interactions of resveratrol with the mitochondrial electron transport chain were revealed. SRT1720, by contrast, stimulated incorporation of (13)C into Krebs cycle intermediates and reduced incorporation into lactate, although the inhibitor EX527 paradoxically also increased Krebs cycle (13)C incorporation. In summary, the various SIRT1 modulators show distinct acute effects on oxidative metabolism. The strong effects of resveratrol on the mitochondrial respiratory chain and on glycolysis suggest that caution should be used in attempts to increase bioavailability of this compound in the CNS.

Shared intermediate phenotypes for schizophrenia and bipolar disorder: neuroanatomical features of subtypes distinguished by executive dysfunction.

Shepherd AM, Quidé Y, Laurens KR, O'Reilly N, Rowland JE, Mitchell PB, Carr VJ, Green MJ

Neuroanatomical commonalities are evident among patients with schizophrenia-spectrum disorders and BD-I with working memory deficits. Reduced inferior frontal lobe volume may mediate cognitive deficits shared across the psychosis-mood spectrum.

Regional Gray Matter Volumes Are Related to Concern About Falling in Older People: A Voxel-Based Morphometric Study.

Tuerk C, Zhang H, Sachdev P, Lord SR, Brodaty H, Wen W, Delbaere K

Our study findings show that concern about falling is negatively associated with brain volumes in areas important for emotional control and for motor control, executive functions and visual processing in a large sample of older men and women. Regression analyses suggest that these relationships were primarily accounted for by psychological factors (generalized anxiety and neuroticism) and not by physical fall risk or vision.

Structural MRI Biomarkers of Mild Cognitive Impairment from Young Elders to Centenarians.

Yang Z, Wen W, Jiang J, Crawford JD, Reppermund S, Levitan C, Slavin MJ, Kochan NA, Richmond RL, Brodaty H, Trollor JN, Sachdev PS

Structural MRI distinguishes aMCI, but not naMCI, from CN in elderly individuals. The structures that best distinguish aMCI from CN differ in those <85 from those ≥85, suggesting different neuropathological underpinnings of cognitive impairment in the very old.

Assessment of Eating Behavior Disturbance and Associated Neural Networks in Frontotemporal Dementia.

Ahmed RM, Irish M, Henning E, Dermody N, Bartley L, Kiernan MC, Piguet O, Farooqi S, Hodges JR

To define the severity of abnormal eating behavior and sucrose preference and their neural correlates in patients with behavioral variant FTD (bvFTD) and semantic dementia. Marked hyperphagia is restricted to bvFTD, present in all patients with this diagnosis, and supports its diagnostic value. Differing neural networks control eating behavior in patients with bvFTD and semantic dementia and are likely responsible for the differences seen, with a similar network controlling sucrose preference. These networks share structures that control cognitive-reward, autonomic, neuroendocrine, and visual modulation of eating behavior. Delineating the neural networks involved in mediating these changes in eating behavior may enable treatment of these features in patients with complex medical needs and aid in our understanding of structures that control eating behavior in patients with FTD and healthy individuals.

Energy expenditure in frontotemporal dementia: a behavioural and imaging study.

Ahmed RM, Landin-Romero R, Collet TH, van der Klaauw AA, Devenney E, Henning E, Kiernan MC, Piguet O, Farooqi IS, Hodges JR

Dissociation of Structural and Functional Integrities of the Motor System in Amyotrophic Lateral Sclerosis and Behavioral-Variant Frontotemporal Dementia.

Bae JS, Ferguson M, Tan R, Mioshi E, Simon N, Burrell J, Vucic S, Hodges JR, Kiernan MC, Hornberger M

Cross-correlation of structural and functional data further revealed a neural dissociation of different motor-system regions and tracts covarying with the TMS excitability across both patient groups. The structural and functional motor-system integrities appear to be dissociated between ALS and bvFTD, which represents useful information for the diagnosis of motor-system changes in these two disorders.

Ultrasound imaging of the human medial gastrocnemius muscle: how to orient the transducer so that muscle fascicles lie in the image plane.

Bolsterlee B, Gandevia SC, Herbert RD

The length and pennation of muscle fascicles are frequently measured using ultrasonography. Conventional ultrasonography imaging methods only provide two-dimensional images of muscles, but muscles have complex three-dimensional arrangements. The most accurate measurements will be obtained when the ultrasound transducer is oriented so that endpoints of a fascicle lie on the ultrasound image plane and the image plane is oriented perpendicular to the aponeurosis, but little is known about how to find this optimal transducer orientation in the frequently-studied medial gastrocnemius muscle. In the current study, we determined the optimal transducer orientation at 9 sites in the medial gastrocnemius muscle of 8 human subjects by calculating the angle of misalignment between three-dimensional muscle fascicles, reconstructed from diffusion tensor images, and the plane of a virtual ultrasound image. The misalignment angle was calculated for a range of tilts and rotations of the ultrasound transducer relative to a reference orientation that was perpendicular to the skin and parallel to the tibia. With the transducer in the reference orientation, the misalignment was substantial (mean across sites and subjects of 6.5°, range 1.4 to 20.2°). However for all sites and subjects a near-optimal alignment (on average 2.6°, range 0.5° to 6.0°) could be achieved by maintaining 0° tilt and applying a small rotation (typically less than 10°). On the basis of these data we recommend that ultrasonographic measurements of medial gastrocnemius muscle fascicle architecture be obtained, at least for relaxed muscles under static conditions, with the transducer oriented perpendicular to the skin and nearly parallel to the tibia.

Effect of Transducer Orientation on Errors in Ultrasound Image-Based Measurements of Human Medial Gastrocnemius Muscle Fascicle Length and Pennation.

Bolsterlee B, Gandevia SC, Herbert RD

Ultrasound imaging is often used to measure muscle fascicle lengths and pennation angles in human muscles in vivo. Theoretically the most accurate measurements are made when the transducer is oriented so that the image plane aligns with muscle fascicles and, for measurements of pennation, when the image plane also intersects the aponeuroses perpendicularly. However this orientation is difficult to achieve and usually there is some degree of misalignment. Here, we used simulated ultrasound images based on three-dimensional models of the human medial gastrocnemius, derived from magnetic resonance and diffusion tensor images, to describe the relationship between transducer orientation and measurement errors. With the transducer oriented perpendicular to the surface of the leg, the error in measurement of fascicle lengths was about 0.4 mm per degree of misalignment of the ultrasound image with the muscle fascicles. If the transducer is then tipped by 20°, the error increases to 1.1 mm per degree of misalignment. For a given degree of misalignment of muscle fascicles with the image plane, the smallest absolute error in fascicle length measurements occurs when the transducer is held perpendicular to the surface of the leg. Misalignment of the transducer with the fascicles may cause fascicle length measurements to be underestimated or overestimated. Contrary to widely held beliefs, it is shown that pennation angles are always overestimated if the image is not perpendicular to the aponeurosis, even when the image is perfectly aligned with the fascicles. An analytical explanation is provided for this finding.

Effect of head and jaw position on respiratory-related motion of the genioglossus.

Cai M, Brown EC, Hatt A, Cheng S, Bilston LE

Head and jaw position influence upper airway patency and electromyographic (EMG) activity of the main upper airway dilator muscle, the genioglossus. However, it is not known whether changes in genioglossus EMG activity translate into altered muscle movement during respiration. The aim of this study was to determine the influence of head and jaw position on dilatory motion of the genioglossus in healthy adult men during quiet breathing by measuring the displacement of the posterior tongue in six positions–neutral, head extension, head rotation, head flexion, mouth opening, and mandibular advancement. Respiratory-related motion of the genioglossus was imaged with spatial modulation of magnetization (SPAMM) in 12 awake male participants. Tissue displacement was quantified with harmonic phase (HARP) analysis. The genioglossus moved anteriorly beginning immediately before or during inspiration, and there was greater movement in the oropharynx than in the velopharynx in all positions. Anterior displacements of the oropharyngeal tongue varied between neutral head position (0.81 ± 0.41 mm), head flexion (0.62 ± 0.45 mm), extension (0.39 ± 0.19 mm), axial rotation (0.39 ± 0.2 mm), mouth open (1.24 ± 0.72 mm), and mandibular advancement (1.08 ± 0.65 mm). Anteroposterior displacement increased in the mouth-open position and decreased in the rotated position relative to cross-sectional area (CSA) (P = 0.002 and 0.02, respectively), but CSA did not independently predict anteroposterior movement overall (P = 0.057). The findings of this study suggest that head position influences airway dilation during inspiration and may contribute to variation in airway patency in different head positions.

Zopiclone Increases the Arousal Threshold without Impairing Genioglossus Activity in Obstructive Sleep Apnea.

Carter SG, Berger MS, Carberry JC, Bilston LE, Butler JE, Tong BK, Martins RT, Fisher LP, McKenzie DK, Grunstein RR, Eckert DJ

To determine the effects of the nonbenzodiazepine sedative zopiclone on the threshold to arousal with increasing respiratory effort and genioglossus muscle activity and to examine potential physiological factors mediating disparate effects of zopiclone on obstructive sleep apnea (OSA) severity between patients. In a group of patients with predominantly severe OSA, zopiclone increased the arousal threshold without reducing genioglossus muscle activity or its responsiveness to negative pharyngeal pressure. These properties may be beneficial in some patients with OSA with certain pathophysiological characteristics but may worsen hypoxemia in others.

Material specific lateralization of medial temporal lobe function: An fMRI investigation.

Dalton MA, Hornberger M, Piguet O

The theory of material specific lateralization of memory function posits that left and right MTL regions are asymmetrically involved in mnemonic processing of verbal and nonverbal material respectively. Lesion and functional imaging (fMRI) studies provide robust evidence for a left MTL asymmetry in the verbal memory domain. Evidence for a right MTL/nonverbal asymmetry is not as robust. A handful of fMRI studies have investigated this issue but have generally utilised nonverbal stimuli which are amenable to semantic elaboration. This fMRI study aimed to investigate the neural correlates of recognition memory processing in 20 healthy young adults (mean age = 26 years) for verbal stimuli and nonverbal stimuli that were specifically designed to minimize verbalisation. Analyses revealed that the neural correlates of recognition memory processing for verbal and nonverbal stimuli were differentiable and asymmetrically recruited the left and right MTL respectively. The right perirhinal cortex and hippocampus were preferentially involved in successful recognition memory of items devoid of semantic information. In contrast, the left anterior hippocampus was preferentially involved in successful recognition memory of stimuli which contained semantic meaning. These results suggest that the left MTL is preferentially involved in mnemonic processing of verbal/semantic information. In contrast, the right MTL is preferentially involved in visual/non-semantic mnemonic processing. We propose that during development, the left MTL becomes specialised for verbal mnemonic processing due to its proximity with left lateralised cortical language processing areas while visual/non-semantic mnemonic processing gets 'crowded out' to become predominantly, but not completely, the domain of the right MTL.

The neural correlates of auditory and visuospatial span in logopenic progressive aphasia and Alzheimer's disease.

Foxe D, Leyton CE, Hodges JR, Burrell JR, Irish M, Piguet O

This study demonstrates that while lv-PPA and AD commonly share the same underlying neuropathology, their span profiles are distinct and are mediated by divergent patterns of cortical degeneration.

Diurnal cortisol variation and cortisol response to an MRI stressor in schizophrenia and bipolar disorder.

Girshkin L, O'Reilly N, Quidé Y, Teroganova N, Rowland JE, Schofield PR, Green MJ

Markers of HPA axis function, including diurnal cortisol rhythm and cortisol responses to stress or pharmacological manipulation, are increasingly reported as disrupted in schizophrenia (SZ) and bipolar disorder (BD). However, there has been no direct comparison of cortisol responses to stress in SZ and BD in the same study, and associations between cortisol dysfunction and illness characteristics remain unclear. In this study we used spline embedded linear mixed models to examine cortisol levels of SZ and BD participants at waking, during the first 45min after waking (representing the cortisol awakening response; CAR), during the period of rapid cortisol decline post the awakening response, and in reaction to a stressor (MRI scan), relative to healthy controls (HC). Contrary to expectations, neither SZ nor BD showed differences in waking cortisol levels, CAR, or immediate post-CAR decline compared to HC; however, waking cortisol levels were greater in BD relative to SZ. In response to the MRI stressor, the SZ group showed a significant absence of the expected increase in cortisol responsivity to stress, which was seen in both the BD and HC groups. Clinical factors affecting the CAR differed between SZ and BD. In SZ, higher antipsychotic medication dosage was associated with a steeper incline of the CAR, while greater positive symptom severity was associated with a more blunted CAR, and greater levels of anxiety were associated with the blunted cortisol response to stress. In BD, longer illness duration was associated with a steeper incline in CAR and lower levels of waking cortisol. These results suggest that cortisol responses may normalize with medication (in SZ) and longer illness duration (in BD), in line with findings of aberrant cortisol levels in the early stages of psychotic disorders.

Effects of 12 Months Continuous Positive Airway Pressure on Sympathetic Activity Related Brainstem Function and Structure in Obstructive Sleep Apnea.

Henderson LA, Fatouleh RH, Lundblad LC, McKenzie DK, Macefield VG

Muscle sympathetic nerve activity (MSNA) is greatly elevated in patients with obstructive sleep apnea (OSA) during normoxic daytime wakefulness. Increased MSNA is a precursor to hypertension and elevated cardiovascular morbidity and mortality. However, the mechanisms underlying the high MSNA in OSA are not well understood. In this study we used concurrent microneurography and magnetic resonance imaging to explore MSNA-related brainstem activity changes and anatomical changes in 15 control and 15 OSA subjects before and after 6 and 12 months of continuous positive airway pressure (CPAP) treatment. We found that following 6 and 12 months of CPAP treatment, resting MSNA levels were significantly reduced in individuals with OSA. Furthermore, this MSNA reduction was associated with restoration of MSNA-related brainstem activity and structural changes in the medullary raphe, rostral ventrolateral medulla, dorsolateral pons, and ventral midbrain. This restoration occurred after 6 months of CPAP treatment and was maintained following 12 months CPAP. These findings show that continual CPAP treatment is an effective long-term treatment for elevated MSNA likely due to its effects on restoring brainstem structure and function.

Obstructive Sleep Apnoea and Hypertension: the Role of the Central Nervous System.

Henderson LA, Macefield VG

Preservation of episodic memory in semantic dementia: The importance of regions beyond the medial temporal lobes.

Irish M, Bunk S, Tu S, Kamminga J, Hodges JR, Hornberger M, Piguet O

Episodic memory impairment represents one of the hallmark clinical features of patients with Alzheimer's disease (AD) attributable to the degeneration of medial temporal and parietal regions of the brain. In contrast, a somewhat paradoxical profile of relatively intact episodic memory, particularly for non-verbal material, is observed in semantic dementia (SD), despite marked atrophy of the hippocampus. This retrospective study investigated the neural substrates of episodic memory retrieval in 20 patients with a diagnosis of SD and 21 disease-matched cases of AD and compared their performance to that of 35 age- and education-matched healthy older Controls. Participants completed the Rey Complex Figure and the memory subscale of the Addenbrooke's Cognitive Examination-Revised as indices of visual and verbal episodic recall, respectively. Relative to Controls, AD patients showed compromised memory performance on both visual and verbal memory tasks. In contrast, memory deficits in SD were modality-specific occurring exclusively on the verbal task. Controlling for semantic processing ameliorated these deficits in SD, while memory impairments persisted in AD. Voxel-based morphometry analyses revealed significant overlap in the neural correlates of verbal episodic memory in AD and SD with predominantly anteromedial regions, including the bilateral hippocampus, strongly implicated. Controlling for semantic processing negated this effect in SD, however, a distributed network of frontal, medial temporal, and parietal regions was implicated in AD. Our study corroborates the view that episodic memory deficits in SD arise very largely as a consequence of the conceptual loading of traditional tasks. We propose that the functional integrity of frontal and parietal regions enables new learning to occur in SD in the face of significant hippocampal and anteromedial temporal lobe pathology, underscoring the inherent complexity of the episodic memory circuitry.

Neural Substrates of Semantic Prospection - Evidence from the Dementias.

Irish M, Eyre N, Dermody N, O'Callaghan C, Hodges JR, Hornberger M, Piguet O

The ability to envisage personally relevant events at a future time point represents an incredibly sophisticated cognitive endeavor and one that appears to be intimately linked to episodic memory integrity. Far less is known regarding the neurocognitive mechanisms underpinning the capacity to envisage non-personal future occurrences, known as semantic future thinking. Moreover the degree of overlap between the neural substrates supporting episodic and semantic forms of prospection remains unclear. To this end, we sought to investigate the capacity for episodic and semantic future thinking in Alzheimer's disease (n = 15) and disease-matched behavioral-variant frontotemporal dementia (n = 15), neurodegenerative disorders characterized by significant medial temporal lobe (MTL) and frontal pathology. Participants completed an assessment of past and future thinking across personal (episodic) and non-personal (semantic) domains, as part of a larger neuropsychological battery investigating episodic and semantic processing, and their performance was contrasted with 20 age- and education-matched healthy older Controls. Participants underwent whole-brain T1-weighted structural imaging and voxel-based morphometry analysis was conducted to determine the relationship between gray matter integrity and episodic and semantic future thinking. Relative to Controls, both patient groups displayed marked future thinking impairments, extending across episodic and semantic domains. Analyses of covariance revealed that while episodic future thinking deficits could be explained solely in terms of episodic memory proficiency, semantic prospection deficits reflected the interplay between episodic and semantic processing. Distinct neural correlates emerged for each form of future simulation with differential involvement of prefrontal, lateral temporal, and medial temporal regions. Notably, the hippocampus was implicated irrespective of future thinking domain, with the suggestion of lateralization effects depending on the type of information being simulated. Whereas episodic future thinking related to right hippocampal integrity, semantic future thinking was found to relate to left hippocampal integrity. Our findings support previous observations of significant MTL involvement for semantic forms of prospection and point to distinct neurocognitive mechanisms which must be functional to support future-oriented forms of thought across personal and non-personal contexts.

'Language of the past' - Exploring past tense disruption during autobiographical narration in neurodegenerative disorders.

Irish M, Kamminga J, Addis DR, Crain S, Thornton R, Hodges JR, Piguet O

Compromised retrieval of autobiographical memory (ABM) is well established in neurodegenerative disorders. The recounting of autobiographical events is inextricably linked to linguistic knowledge, yet no study to date has investigated whether tense use during autobiographical narration is disrupted in dementia syndromes. This study investigated the incidence of correct past tense use during ABM narration in patients with Alzheimer's disease (AD, n = 10) and semantic dementia (SD, n = 10) in comparison with healthy older Controls (n = 10). Autobiographical narratives were analysed for episodic content (internal/external) and classified according to tense use (past/present). Across both patient groups, use of the past tense was significantly compromised relative to Controls, with increased levels of off-target present tense verbs observed. Voxel-based morphometry analyses based on structural MRI revealed differential associations between past tense use and regions of grey matter intensity in the brain. Bilateral temporal cortices were implicated in the SD group, whereas frontal, lateral, and medial temporal regions including the right hippocampus emerged in AD. This preliminary study provides the first demonstration of the disruption of specific linguistic constructs during autobiographical narration in AD and SD. Future studies are warranted to clarify at what point in the disease trajectory such deficits in tense use emerge, and whether these deficits are a product or contributing factor in memory disruption in these syndromes.

Adjunctive selective estrogen receptor modulator increases neural activity in the hippocampus and inferior frontal gyrus during emotional face recognition in schizophrenia.

Ji E, Weickert CS, Lenroot R, Kindler J, Skilleter AJ, Vercammen A, White C, Gur RE, Weickert TW

Estrogen has been implicated in the development and course of schizophrenia with most evidence suggesting a neuroprotective effect. Treatment with raloxifene, a selective estrogen receptor modulator, can reduce symptom severity, improve cognition and normalize brain activity during learning in schizophrenia. People with schizophrenia are especially impaired in the identification of negative facial emotions. The present study was designed to determine the extent to which adjunctive raloxifene treatment would alter abnormal neural activity during angry facial emotion recognition in schizophrenia. Twenty people with schizophrenia (12 men, 8 women) participated in a 13-week, randomized, double-blind, placebo-controlled, crossover trial of adjunctive raloxifene treatment (120 mg per day orally) and performed a facial emotion recognition task during functional magnetic resonance imaging after each treatment phase. Two-sample t-tests in regions of interest selected a priori were performed to assess activation differences between raloxifene and placebo conditions during the recognition of angry faces. Adjunctive raloxifene significantly increased activation in the right hippocampus and left inferior frontal gyrus compared with the placebo condition (family-wise error, P<0.05). There was no significant difference in performance accuracy or reaction time between active and placebo conditions. To the best of our knowledge, this study provides the first evidence suggesting that adjunctive raloxifene treatment changes neural activity in brain regions associated with facial emotion recognition in schizophrenia. These findings support the hypothesis that estrogen plays a modifying role in schizophrenia and shows that adjunctive raloxifene treatment may reverse abnormal neural activity during facial emotion recognition, which is relevant to impaired social functioning in men and women with schizophrenia.

Raloxifene increases prefrontal activity during emotional inhibition in schizophrenia based on estrogen receptor genotype.

Kindler J, Weickert CS, Schofield PR, Lenroot R, Weickert TW

Central circuitry responsible for the divergent sympathetic responses to tonic muscle pain in humans.

Kobuch S, Fazalbhoy A, Brown R, Henderson LA, Macefield VG

On the right side? A longitudinal study of left- versus right-lateralized semantic dementia.

Kumfor F, Landin-Romero R, Devenney E, Hutchings R, Grasso R, Hodges JR, Piguet O

The typical presentation of semantic dementia is associated with marked, left predominant anterior temporal lobe atrophy and with changes in language. About 30% of individuals, however, present with predominant right anterior temporal lobe atrophy, usually accompanied by behavioural changes and prosopagnosia. Here, we aimed to establish whether these initially distinct clinical presentations evolve into a similar syndrome at the neural and behavioural level. Thirty-one patients who presented with predominant anterior temporal lobe atrophy were included. Based on imaging, patients were categorized as either predominant left (n = 22) or right (n = 9) semantic dementia. Thirty-three Alzheimer's disease patients and 25 healthy controls were included for comparison. Participants completed the Addenbrooke's Cognitive Examination, a Face and Emotion Processing Battery and the Cambridge Behavioural Inventory, and underwent magnetic resonance imaging annually. Longitudinal neuroimaging analyses showed greater right temporal pole atrophy in left semantic dementia than Alzheimer's disease, whereas right semantic dementia showed greater orbitofrontal and left temporal lobe atrophy than Alzheimer's disease. Importantly, direct comparisons between semantic dementia groups revealed that over time, left semantic dementia showed progressive thinning in the right temporal pole, whereas right semantic dementia showed thinning in the orbitofrontal cortex and anterior cingulate. Behaviourally, longitudinal analyses revealed that general cognition declined in all patients. In contrast, patients with left and right semantic dementia showed greater emotion recognition decline than Alzheimer's disease. In addition, left semantic dementia showed greater motivation loss than Alzheimer's disease. Correlational analyses revealed that emotion recognition was associated with right temporal pole, right medial orbitofrontal and right fusiform integrity, while changes in motivation were associated with right temporal pole cortical thinning. While left and right semantic dementia show distinct profiles at presentation, both phenotypes develop deficits in emotion recognition and behaviour. These findings highlight the pervasive socio-emotional deficits in frontotemporal dementia, even in patients with an initial language presentation. These changes reflect right anterior temporal and orbitofrontal cortex degeneration, underscoring the role of these regions in social cognition and behaviour.

Disease-specific patterns of cortical and subcortical degeneration in a longitudinal study of Alzheimer's disease and behavioural-variant frontotemporal dementia.

Landin-Romero R, Kumfor F, Leyton CE, Irish M, Hodges JR, Piguet O

These results indicate that atrophy in the posterior cingulate and the striatum diverges with disease progression in these dementia syndromes and may represent a potential diagnostic biomarker for tracking rates of progression of AD and bvFTD. These findings may help inform future drug trials by identifying appropriate outcome measures to quantify drug efficacy and their ability to modulate disease progression over time.

White matter hyperintensities are a core feature of Alzheimer's disease: Evidence from the dominantly inherited Alzheimer network.

Lee S, Viqar F, Zimmerman ME, Narkhede A, Tosto G, Benzinger TL, Marcus DS, Fagan AM, Goate A, Fox NC, Cairns NJ, Holtzman DM, Buckles V, Ghetti B, McDade E, Martins RN, Saykin AJ, Masters CL, Ringman JM, Ryan NS, Förster S, Laske C, Schofield PR, Sperling RA, Salloway S, Correia S, Jack C, Weiner M, Bateman RJ, Morris JC, Mayeux R, Brickman AM,

White matter hyperintensities (WMHs) are areas of increased signal on T2-weighted magnetic resonance imaging (MRI) scans that most commonly reflect small vessel cerebrovascular disease. Increased WMH volume is associated with risk and progression of Alzheimer's disease (AD). These observations are typically interpreted as evidence that vascular abnormalities play an additive, independent role contributing to symptom presentation, but not core features of AD. We examined the severity and distribution of WMH in presymptomatic PSEN1, PSEN2, and APP mutation carriers to determine the extent to which WMH manifest in individuals genetically determined to develop AD.

Distinctive pathological mechanisms involved in primary progressive aphasias.

Leyton CE, Britton AK, Hodges JR, Halliday GM, Kril JJ

Primary progressive aphasia (PPA) comprises a heterogeneous group of neurodegenerative conditions that can be classified in three cliniconeuroanatomic syndromes. Limited information exists, however, about patterns of neuropathologic spreading and microscopic changes underpinning each syndrome. We performed an analysis of a longitudinal in vivo cohort and a postmortem PPA cohort to investigate neurodegeneration over time and to quantify microscopic changes in key language brain areas. The longitudinal analyses demonstrated distinctive patterns of topological extension of brain atrophy. Although semantic variant (sv-PPA) showed an eccentric pattern, nonfluent and/or agrammatic (nfv-PPA) and logopenic (lv-PPA) variants showed additional multifocal extension. The quantitative pathology showed that sv-PPA had neuronal loss and thinning in BA 38, whereas nfv-PPA showed thinning in BA 44/45 and evidence of microscopic involvement in BA 40/22. Although lv-PPA showed neuronal loss focused on BA 40/22, imaging results demonstrated widespread left-sided brain atrophy. These analyses provide an account of the pathologic process whereby each variant has stereotypical patterns of brain atrophy extension, which is largely determined by the specific pathologic type.

"Real-time" imaging of cortical and subcortical sites of cardiovascular control: concurrent recordings of sympathetic nerve activity and fMRI in awake subjects.

Macefield VG, Henderson LA

We review our approach to functionally identifying cortical and subcortical areas involved in the generation of spontaneous fluctuations in sympathetic outflow to muscle or skin. We record muscle sympathetic nerve activity (MSNA) or skin sympathetic nerve activity (SSNA), via a tungsten microelectrode inserted percutaneously into the common peroneal nerve, at the same time as performing functional magnetic resonance imaging (fMRI) of the brain. By taking advantage of the neurovascular coupling delay associated with BOLD (blood oxygen level dependent) fMRI, and the delay associated with conduction of a burst of sympathetic impulses to the peripheral recording site, we can identify structures in which BOLD signal intensity covaries with MSNA or SSNA. Using this approach, we found MSNA-coupled increases in BOLD signal intensity in the mid-insula and dorsomedial hypothalamus on the left side, and in dorsolateral prefrontal cortex, posterior cingulate cortex, precuneus, ventromedial hypothalamus and rostral ventrolateral medulla on both sides. Conversely, spontaneous bursts of SSNA were positively correlated with BOLD signal intensity in the ventromedial thalamus and posterior insula on the left side, and in the anterior insula, orbitofrontal cortex and frontal cortex on the right side, and in the mid-cingulate cortex and precuneus on both sides. Inverse relationships were observed between MSNA and BOLD signal intensity in the right ventral insula, nucleus tractus solitarius and caudal ventrolateral medulla, and between SSNA and signal intensity in the left orbitofrontal cortex. These results emphasize the contributions of cortical regions of the brain to sympathetic outflow in awake human subjects, and the extensive interactions between cortical and subcortical regions in the ongoing regulation of sympathetic nerve activity to muscle and skin in awake human subjects.

Fair play: social norm compliance failures in behavioural variant frontotemporal dementia.

O'Callaghan C, Bertoux M, Irish M, Shine JM, Wong S, Spiliopoulos L, Hodges JR, Hornberger M

Adherence to social norms is compromised in a variety of neuropsychiatric conditions. Functional neuroimaging studies have investigated social norm compliance in healthy individuals, leading to the identification of a network of fronto-subcortical regions that underpins this ability. However, there is a lack of corroborative evidence from human lesion models investigating the structural anatomy of norm compliance across this fronto-subcortical network. To address this, we developed a neuroeconomic task to investigate social norm compliance in a neurodegenerative lesion model: behavioural variant frontotemporal dementia, a condition characterized by gross social dysfunction. The task assessed norm compliance across three behaviours that are well-studied in the neuroeconomics literature: fairness, prosocial and punishing behaviours. We administered our novel version of the Ultimatum Game in 22 patients with behavioural variant frontotemporal dementia and 22 age-matched controls, to assess how decision-making behaviour was modulated in response to (i) fairness of monetary offers; and (ii) social context of monetary offers designed to produce either prosocial or punishing behaviours. Voxel-based morphometry was used to characterize patterns of grey matter atrophy associated with task performance. Acceptance rates between patients and controls were equivalent when only fairness was manipulated. However, patients were impaired in modulating their decisions in response to social contextual information. Patients' performance in the punishment condition was consistent with a reduced tendency to engage in punishment; this was associated with decreased grey matter volume in the anterior cingulate, orbitofrontal cortex, left dorsolateral prefrontal cortex and right inferior frontal gyrus. In the prosocial condition, patients' performance suggested a reduced expression of prosocial behaviour, associated with decreased grey matter in the anterior insula, lateral orbitofrontal cortex, anterior cingulate and dorsal striatum. Acceptance rates in the Ultimatum Game were also significantly related to impairments in the everyday expression of empathic concern. In conclusion, we demonstrate that compliance to basic social norms (fairness) can be maintained in behavioural variant frontotemporal dementia; however, more complex normative behaviours (prosociality, punishment) that require integration of social contextual information are disrupted in association with atrophy in key fronto-striatal regions. These results suggest that the integration of social contextual information to guide normative behaviour is uniquely impaired in behavioural variant frontotemporal dementia, and may explain other common features of the condition including gullibility and impaired empathy. Our findings also converge with previous functional neuroimaging investigations in healthy individuals and provide the first description of the structural anatomy of social norm compliance in a neurodegenerative lesion model.

Association of serum VEGF levels with prefrontal cortex volume in schizophrenia.

Pillai A, Howell KR, Ahmed AO, Weinberg D, Allen KM, Bruggemann J, Lenroot R, Liu D, Galletly C, Weickert CS, Weickert TW

A large body of evidence indicates alterations in brain regional cellular energy metabolism and blood flow in schizophrenia. Among the different molecules regulating blood flow, vascular endothelial growth factor (VEGF) is generally accepted as the major factor involved in the process of angiogenesis. In the present study, we examined whether peripheral VEGF levels correlate with changes in the prefrontal cortex (PFC) volume in patients with schizophrenia and in healthy controls. Whole-blood samples were obtained from 96 people with schizophrenia or schizoaffective disorder and 83 healthy controls. Serum VEGF protein levels were analyzed by enzyme-linked immunosorbent assay, whereas quantitative PCR was performed to measure interleukin-6 (IL-6, a pro-inflammatory marker implicated in schizophrenia) mRNA levels in the blood samples. Structural magnetic resonance imaging scans were obtained using a 3T Achieva scanner on a subset of 59 people with schizophrenia or schizoaffective disorder and 65 healthy controls, and prefrontal volumes were obtained using FreeSurfer software. As compared with healthy controls, individuals with schizophrenia had a significant increase in log-transformed mean serum VEGF levels (t(177)=2.9, P=0.005). A significant inverse correlation (r=-0.40, P=0.002) between serum VEGF and total frontal pole volume was found in patients with schizophrenia/schizoaffective disorder. Moreover, we observed a significant positive association (r=0.24, P=0.03) between serum VEGF and IL-6 mRNA levels in patients with schizophrenia. These findings suggest an association between serum VEGF and inflammation, and that serum VEGF levels are related to structural abnormalities in the PFC of people with schizophrenia.

The Relationship Between Plasma Aβ Levels, Cognitive Function and Brain Volumetrics: Sydney Memory and Ageing Study.

Poljak A, Crawford JD, Smythe GA, Brodaty H, Slavin MJ, Kochan NA, Trollor JN, Wen W, Mather KA, Assareh AA, Ng PC, Sachdev PS

Determine whether (1) a relationship exists between plasma amyloid-β (Aβ)1- 40 and 1-42 peptide levels, brain volumetrics and cognitive performance in elderly individuals with and without amnestic mild cognitive impairment (aMCI), (2) plasma Aβ peptide levels differ between apolipoprotein E (APOE) ε4 carriers and non-carriers and (3) longitudinal changes in cognition and brain volume relate to Aβ levels. Plasma Aβ levels and the Aβ1-42/1-40 ratio are related to cognition and hippocampal volumes, with differential associations of Aβ1-40 and Aβ1-42 in ε4 carriers and non-carriers. These data support the Aβ sink model of AD pathology, and suggest that plasma Aβ measures may serve as biomarkers of AD.

Effects of childhood trauma on working memory in affective and non-affective psychotic disorders.

Quidé Y, O'Reilly N, Rowland JE, Carr VJ, Elzinga BM, Green MJ

Brain volume loss contributes to arousal and empathy dysregulation following severe traumatic brain injury.

Rushby JA, McDonald S, Fisher AC, Kornfeld EJ, De Blasio FM, Parks N, Piguet O

Quantitative Amyloid Imaging in Autosomal Dominant Alzheimer's Disease: Results from the DIAN Study Group.

Su Y, Blazey TM, Owen CJ, Christensen JJ, Friedrichsen K, Joseph-Mathurin N, Wang Q, Hornbeck RC, Ances BM, Snyder AZ, Cash LA, Koeppe RA, Klunk WE, Galasko D, Brickman AM, McDade E, Ringman JM, Thompson PM, Saykin AJ, Ghetti B, Sperling RA, Johnson KA, Salloway SP, Schofield PR, Masters CL, Villemagne VL, Fox NC, Förster S, Chen K, Reiman EM, Xiong C, Marcus DS, Weiner MW, Morris JC, Bateman RJ, Benzinger TL,

Amyloid imaging plays an important role in the research and diagnosis of dementing disorders. Substantial variation in quantitative methods to measure brain amyloid burden exists in the field. The aim of this work is to investigate the impact of methodological variations to the quantification of amyloid burden using data from the Dominantly Inherited Alzheimer's Network (DIAN), an autosomal dominant Alzheimer's disease population. Cross-sectional and longitudinal [11C]-Pittsburgh Compound B (PiB) PET imaging data from the DIAN study were analyzed. Four candidate reference regions were investigated for estimation of brain amyloid burden. A regional spread function based technique was also investigated for the correction of partial volume effects. Cerebellar cortex, brain-stem, and white matter regions all had stable tracer retention during the course of disease. Partial volume correction consistently improves sensitivity to group differences and longitudinal changes over time. White matter referencing improved statistical power in the detecting longitudinal changes in relative tracer retention; however, the reason for this improvement is unclear and requires further investigation. Full dynamic acquisition and kinetic modeling improved statistical power although it may add cost and time. Several technical variations to amyloid burden quantification were examined in this study. Partial volume correction emerged as the strategy that most consistently improved statistical power for the detection of both longitudinal changes and across-group differences. For the autosomal dominant Alzheimer's disease population with PiB imaging, utilizing brainstem as a reference region with partial volume correction may be optimal for current interventional trials. Further investigation of technical issues in quantitative amyloid imaging in different study populations using different amyloid imaging tracers is warranted.

Into the future with little past: exploring mental time travel in a patient with damage to the mammillary bodies/fornix.

Tedder J, Miller L, Tu S, Hornberger M, Lah S

Remembering the past and imaging the future are both manifestations of 'mental time travel'. These processes have been found to be impaired in patients with bilateral hippocampal lesions. Here, we examined the question of whether future thinking is affected by other Papez circuit lesions, namely: damage to the mammillary bodies/fornix. This dissociation of past and future events' performance after mammillary body and fornix damage is at odds with the findings of the majority of patients with adult onset hippocampal amnesia. It suggests that these non-hippocampal regions of the Papez circuit are only critical for past event retrieval and not for the generation of possible future events.

Cognitive Subtypes of Schizophrenia Characterized by Differential Brain Volumetric Reductions and Cognitive Decline.

Weinberg D, Lenroot R, Jacomb I, Allen K, Bruggemann J, Wells R, Balzan R, Liu D, Galletly C, Catts SV, Weickert CS, Weickert TW

To confirm previous findings related to IQ-based subgroups of patients with schizophrenia in an independent sample and extend those findings to determine the extent to which brain volumetric differences correspond to the IQ-based subgroups. Using an independent sample, we obtained proportions in each IQ-based subgroup that were similar to our previous work. Inferior parietal volume reduction was characteristic of schizophrenia relative to controls, and the severely deteriorated IQ group had widespread volumetric reductions. Classifying cognitive heterogeneity in schizophrenia provides a platform to better characterize the neurobiological underpinnings of the illness and its treatment.

The self-reference effect in dementia: Differential involvement of cortical midline structures in Alzheimer's disease and behavioural-variant frontotemporal dementia.

Wong S, Irish M, Leshikar ED, Duarte A, Bertoux M, Savage G, Hodges JR, Piguet O, Hornberger M

Age-associated differences on structural brain MRI in nondemented individuals from 71 to 103 years.

Yang Z, Wen W, Jiang J, Crawford JD, Reppermund S, Levitan C, Slavin MJ, Kochan NA, Richmond RL, Brodaty H, Trollor JN, Sachdev PS

Successful brain aging in the oldest old (≥90 years) is underexplored. This study examined cross-sectional brain morphological differences from 8th to 11th decades of life in nondemented individuals by high-resolution magnetic resonance imaging. Two hundred seventy-seven nondemented community-dwelling participants (71-103 years) from Sydney Memory and Ageing Study and Sydney Centenarian Study comprised the sample, including a subsample of 160 cognitively high-functioning elders. Relationships between age and magnetic resonance imaging-derived measurements were studied using general linear models; and structural profiles of the ≥90 years were delineated. In full sample and the subsample, significant linear negative relationship of gray matter with age was found, with the greatest age effects in the medial temporal lobe and parietal and occipital cortices. This pattern was further confirmed by comparing directly the ≥90 years to the 71-89 years groups. Significant quadratic age effects on total white matter and white matter hyperintensities were observed. Our study demonstrated heterogeneous differences across brain regions between the oldest old and young old, with an emphasis on hippocampus, temporoposterior cortex, and white matter hyperintensities.

Structural MRI Biomarkers of Mild Cognitive Impairment from Young Elders to Centenarians.

Yang Z, Wen W, Jiang J, Crawford JD, Reppermund S, Levitan C, Slavin MJ, Kochan NA, Richmond RL, Brodaty H, Trollor JN, Sachdev PS

Structural MRI distinguishes aMCI, but not naMCI, from CN in elderly individuals. The structures that best distinguish aMCI from CN differ in those <85 from those ≥85, suggesting different neuropathological underpinnings of cognitive impairment in the very old.

Cortical influences on brainstem circuitry responsible for conditioned pain modulation in humans.

Youssef AM, Macefield VG, Henderson LA

Conditioned pain modulation (CPM) is a powerful endogenous analgesic mechanism which can completely inhibit incoming nociceptor signals at the primary synapse. The circuitry responsible for CPM lies within the brainstem and involves the subnucleus reticularis dorsalis (SRD). While the brainstem is critical for CPM, the cortex can significantly modulate its expression, likely via the brainstem circuitry critical for CPM. Since higher cortical regions such as the anterior, mid-cingulate, and dorsolateral prefrontal cortices are activated by noxious stimuli and show reduced activations during other analgesic responses, we hypothesized that these regions would display reduced responses during CPM analgesia. Furthermore, we hypothesized that functional connectivity strength between these cortical regions and the SRD would be stronger in those that express CPM analgesia compared with those that do not. We used functional magnetic resonance imaging to determine sites recruited during CPM expression and their influence on the SRD. A lack of CPM analgesia was associated with greater signal intensity increases during each test stimulus in the presence of the conditioning stimulus compared to test stimuli alone in the mid-cingulate and dorsolateral prefrontal cortices and increased functional connectivity with the SRD. In contrast, those subjects exhibiting CPM analgesia showed no change in the magnitude of signal intensity increases in these cortical regions or strength of functional connectivity with the SRD. These data suggest that during multiple or widespread painful stimuli, engagement of the prefrontal and cingulate cortices prevents the generation of CPM analgesia, raising the possibility altered responsiveness in these cortical regions underlie the reduced CPM observed in individuals with chronic pain. Hum Brain Mapp 37:2630-2644, 2016. © 2016 Wiley Periodicals, Inc.

Pain inhibits pain; human brainstem mechanisms.

Youssef AM, Macefield VG, Henderson LA

Conditioned pain modulation is a powerful analgesic mechanism, occurring when a painful stimulus is inhibited by a second painful stimulus delivered at a different body location. Reduced conditioned pain modulation capacity is associated with the development of some chronic pain conditions and the effectiveness of some analgesic medications. Human lesion studies show that the circuitry responsible for conditioned pain modulation lies within the caudal brainstem, although the precise nuclei in humans remain unknown. We employed brain imaging to determine brainstem sites responsible for conditioned pain modulation in 54 healthy individuals. In all subjects, 8 noxious heat stimuli (test stimuli) were applied to the right side of the mouth and brain activity measured using functional magnetic resonance imaging. This paradigm was then repeated. However, following the fourth noxious stimulus, a separate noxious stimulus, consisting of an intramuscular injection of hypertonic saline into the leg, was delivered (conditioning stimulus). During this test and conditioning stimulus period, 23 subjects displayed conditioned pain modulation analgesia whereas 31 subjects did not. An individual's analgesic ability was not influenced by gender, pain intensity levels of the test or conditioning stimuli or by psychological variables such as pain catastrophizing or fear of pain. Brain images were processed using SPM8 and the brainstem isolated using the SUIT toolbox. Significant increases in signal intensity were determined during each test stimulus and compared between subjects that did and did not display CPM analgesia (p<0.05, small volume correction). The expression of analgesia was associated with reduction in signal intensity increases during each test stimulus in the presence of the conditioning stimulus in three brainstem regions: the caudalis subdivision of the spinal trigeminal nucleus, i.e., the primary synapse, the region of the subnucleus reticularis dorsalis and in the dorsolateral pons in the region of the parabrachial nucleus. Furthermore, the magnitudes of these signal reductions in all three brainstem regions were significantly correlated to analgesia magnitude. Defining conditioned pain modulation circuitry provides a framework for the future investigations into the neural mechanisms responsible for the maintenance of persistent pain conditions thought to involve altered analgesic circuitry.

Comparison of measurements of medial gastrocnemius architectural parameters from ultrasound and diffusion tensor images.

Bolsterlee B, Veeger HE, van der Helm FC, Gandevia SC, Herbert RD

In vivo measurements of muscle architecture provide insight into inter-individual differences in muscle function and could be used to personalise musculoskeletal models. When muscle architecture is measured from ultrasound images, as is frequently done, it is assumed that fascicles are oriented in the image plane and, for some measurements, that the image plane is perpendicular to the aponeurosis at the intersection of fascicle and aponeurosis. This study presents an in vivo validation of these assumptions by comparing ultrasound image plane orientation to three-dimensional reconstructions of muscle fascicles and aponeuroses obtained with diffusion tensor imaging (DTI) and high-resolution anatomical MRI scans. It was found that muscle fascicles were oriented on average at 5.5±4.1° to the ultrasound image plane. On average, ultrasound yielded similar measurements of fascicle lengths to DTI (difference <3mm), suggesting that the measurements were unbiased. The absolute difference in length between any pair of measurements made with ultrasound and DTI was substantial (10mm or 20% of the mean), indicating that the measurements were imprecise. Pennation angles measured with ultrasound were significantly smaller than those measured with DTI (mean difference 6°). This difference was apparent only at the superficial insertion of the muscle fascicles so it was probably due to pressure on the skin applied by the ultrasound probes. It is concluded that ultrasound measurements of deep pennation angles and fascicle lengths in the medial gastrocnemius are unbiased but have a low precision and that superficial pennation angles are underestimated by approximately 10°. The low precision limits the use of ultrasound to personalise fascicle length in musculoskeletal models.