Spectral Changes of EEG Following a 6-Week Low-Dose Oral Ketamine Treatment in Adults With Major Depressive Disorder and Chronic Suicidality.

BACKGROUND: Ketamine has considerable therapeutic potential in alleviating major depressive disorder and chronic suicidality. However, the clinical diagnosis of neuropsychiatric disorders requires more robust diagnostic criteria. Electroencephalography (EEG) has shown promise in classifying depressive and suicidal patients from healthy individuals. The present study aimed to identify changes in the spectral properties of EEG in patients with major depressive disorder and chronic suicidality after completing the 6-week Oral Ketamine Trial on Suicidality with follow-up occurring 4 weeks after final ketamine treatment and determine associations between EEG spectral output and clinical symptoms. METHODS: Participants (n = 25) had 4-minute eyes closed resting state EEG recorded at frontal, temporal, centro-parietal, and occipital regions. Spectral analysis was performed with Welch's power spectrum density method, and the power of 4 distinct frequency bands was analyzed: theta, alpha, low-beta, and high-beta. Correlation analyses between changes in clinical symptoms and spectral power were conducted using Spearman's ranked correlation. RESULTS: Between pre- and posttreatment, only centro-parietal alpha power decreased. Between posttreatment and follow-up, centro-parietal alpha increased again in addition to increases in temporal alpha, centro-parietal and temporal theta, and occipital low-beta and decreases in occipital theta and temporal low-beta. Additionally, the decrease of occipital theta positively correlated with clinical subscales for depression and stress. CONCLUSIONS: EEG spectral analysis revealed significant changes in theta, alpha, and low-beta frequency bands. Alpha band showed initial changes after treatment; however, this trended back toward baseline levels after the treatment cessation. In contrast, theta and low-beta showed significant power changes only after the treatment had ended.

Early adolescent psychological distress and cognition, correlates of resting-state EEG, interregional phase-amplitude coupling.

Delineating neurobiological markers of youth mental health is crucial for early identification and treatment. One promising marker is phase-amplitude coupling (PAC), cross-frequency coupling between the phase of slower oscillatory activity and the amplitude of faster oscillatory activity in the brain. Prior research has demonstrated that PAC is associated with both cognition and mental health and can be modulated using neurostimulation. However, to date research investigating PAC has focused primarily on adults, and only within-region theta-gamma coupling in the context of mental health. We investigated associations between interregional resting-state PAC (posterior-anterior cortex), and cognition and psychological distress in N = 77 (Mage = 12.58 years, SD = 0.31; 51 % female) 12-year-olds. Firstly, while left theta-beta PAC showed a moderate positive correlation (r = 0.529, p < .01), right theta-gamma PAC showed a weak positive correlation, with psychological distress (r = 0.283, p < .05). In terms of cognition, moderate correlations were observed between: (i) increased left theta-beta PAC and increased psychomotor speed (r = -0.367, p < .05); (ii) increased left alpha-beta PAC and decreased attention (r = 0.355, p ≤0.01); and (iii) increased left alpha-beta PAC and decreased verbal learning and memory (r = -0.352, p < .01). Whereas weak associations were observed for: (i) increased left alpha-beta PAC and decreased executive functioning scores (r = 0.284, p < .05); and (ii) increased left alpha-gamma PAC and increased attention (r = -0.272, p < .05). The overall findings of this exploratory study are encouraging, although all the correlations were in the weak-to-moderate range and require replication. Further research may confirm interregional resting-state PAC as a biomarker that can help us better understand the link between mental health and cognition in adolescents and improve treatment of cognitive related deficits in mental illness.

Neoadjuvant Radiotherapy Dose Escalation in Locally Advanced Rectal Cancer: a Systematic Review and Meta-analysis of Modern Treatment Approaches and Outcomes.

AIMS: Improving pathological complete response (pCR) rates after neoadjuvant chemoradiotherapy for locally advanced rectal cancer may facilitate surgery-sparing treatment paradigms. Radiotherapy boost has been linked to higher rates of pCR; however, outcomes in moderately escalated inverse-planning studies have not been systematically evaluated. We therefore carried out a systematic review and meta-analysis of radiation dose-escalation studies in the context of neoadjuvant therapy for locally advanced rectal cancer. MATERIALS AND METHODS: A systematic search of Pubmed, EMBASE and Cochrane databases for synonyms of 'rectal cancer', 'radiotherapy' and 'boost' was carried out. Studies were screened for radiotherapy prescription >54 Gy. Prespecified quality assessment was carried out for meta-analysis inclusion suitability. Pooled estimates of pCR, acute toxicity (grade ≥3) and R0 resection rates were determined with random-effects restricted maximum-likelihood estimation. Heterogeneity was assessed with Higgins I2 and Cochran Q statistic. Subset analysis examined outcomes in modern inverse-planning studies. Meta-regression with permutation correction was carried out for each outcome against radiation dose, radiotherapy technique, boost technique, chemotherapy intensification and other patient- and treatment-related cofactors. RESULTS: Forty-nine primary and three follow-up publications were included in the systematic review. Pooled estimates of pCR, toxicity and R0 resection across 37 eligible publications (n = 1817 patients) were 24.1% (95% confidence interval 21.2-27.4%), 11.2% (95% confidence interval 7.2-17.0%) and 90.7% (95% confidence interval 87.9-93.8%). Within inverse-planning studies (17 publications, n = 959 patients), these rates were 25.7% (95% confidence interval 21.0-31.1%), 9.8% (95% confidence interval 4.6-19.7%) and 95.3% (95% confidence interval 91.6-97.4%). Regression analysis did not identify any significant predictor of pCR (P > 0.05). CONCLUSIONS: Radiotherapy dose escalation above 54 Gy is associated with high rates of pCR and does not seem to increase the risk of acute grade ≥3 toxicity events. pCR rates approaching 25% may be achievable utilising moderate escalation (54-60 Gy) with modern inverse-planning techniques; however, a clear dose-response relationship was not identified in regression analysis and additional evidence is awaited given the prevalence of heterogenous single-arm studies to date.

A Review of Modern Radiation Therapy Dose Escalation in Locally Advanced Head and Neck Cancer.

The management of head and neck cancer is complex and often involves multimodality treatment. Certain groups of patients, such as those with inoperable or advanced disease, are at higher risk of treatment failure and may therefore benefit from radiation therapy dose escalation. This can be difficult to achieve without increasing toxicity. However, the combination of modern treatment techniques and increased research into the use of functional imaging modalities that assist with target delineation allows researchers to push this boundary further. This review aims to summarise modern dose escalation trials to identify the impact on disease outcomes and explore the growing role of functional imaging modalities. Studies experimenting with dose escalation above standard fractionated regimens as outlined in National Comprehensive Cancer Network guidelines using photon therapy were chosen for review. Seventeen papers were considered suitable for inclusion in the review. Eight studies investigated nasopharyngeal cancer, with the remainder treating a range of subsites. Six studies utilised functional imaging modalities for target delineation. Doses as high as 85.9 Gy in 2.6 Gy fractions (EQD2 90.2 Gy10) were reportedly delivered with the aid of functional imaging modalities. Dose escalation in nasopharyngeal cancer resulted in 3-year locoregional control rates of 86.6-100% and overall survival of 82-95.2%. For other mucosal primary tumour sites, 3-year locoregional control reached 68.2-85.9% and 48.4-54% for overall survival. There were no clear trends in acute or late toxicity across studies, regardless of dose or addition of chemotherapy. However, small cohort sizes and short follow-up times may have resulted in under-reporting. This review highlights the future possibilities of radiation therapy dose escalation in head and neck cancer and the potential for improved target delineation with careful patient selection and the assistance of functional imaging modalities.

Subcortical brain structure and suicidal behaviour in major depressive disorder: a meta-analysis from the ENIGMA-MDD working group.

The aetiology of suicidal behaviour is complex, and knowledge about its neurobiological mechanisms is limited. Neuroimaging methods provide a noninvasive approach to explore the neural correlates of suicide vulnerability in vivo. The ENIGMA-MDD Working Group is an international collaboration evaluating neuroimaging and clinical data from thousands of individuals collected by research groups from around the world. Here we present analyses in a subset sample (n=3097) for whom suicidality data were available. Prevalence of suicidal symptoms among major depressive disorder (MDD) cases ranged between 29 and 69% across cohorts. We compared mean subcortical grey matter volumes, lateral ventricle volumes and total intracranial volume (ICV) in MDD patients with suicidal symptoms (N=451) vs healthy controls (N=1996) or MDD patients with no suicidal symptoms (N=650). MDD patients reporting suicidal plans or attempts showed a smaller ICV (P=4.12 × 10-3) or a 2.87% smaller volume compared with controls (Cohen's d=-0.284). In addition, we observed a nonsignificant trend in which MDD cases with suicidal symptoms had smaller subcortical volumes and larger ventricular volumes compared with controls. Finally, no significant differences (P=0.28-0.97) were found between MDD patients with and those without suicidal symptoms for any of the brain volume measures. This is by far the largest neuroimaging meta-analysis of suicidal behaviour in MDD to date. Our results did not replicate previous reports of association between subcortical brain structure and suicidality and highlight the need for collecting better-powered imaging samples and using improved suicidality assessment instruments.

Brain responses to mechanical rectal stimulation in patients with faecal incontinence: an fMRI study.

AIM: Continence is dependent on anorectal-brain interactions. Consequently, aberrations of the brain-gut axis may be important in the pathophysiology of faecal incontinence (FI) in certain patients. The aim of this study was to assess the feasibility of recording brain responses to rectal mechanical stimulation in patients with FI using functional magnetic resonance imaging (fMRI). METHOD: A prospective, cohort pilot study was performed to assess brain responses during rectal stimulation in 14 patients [four men, mean (SD) age 62 (15) years]. Blood oxygen level dependent (BOLD) signals were measured by fMRI during rest and mechanical distension, involving random repetitions of isobaric phasic rectal distensions at fixed (15 and 45 mmHg) and variable (10% above sensory perception threshold) pressures. RESULTS: Increases in BOLD signals in response to high pressure rectal distension (45 mmHg) and maximum toleration were observed in the cingulate gyrus, thalamus, insular cortex, inferior frontal gyrus, cerebellum, caudate nucleus, supramarginal gyrus, putamen and amygdala. Additionally, activation of the supplementary motor cortex and caudate nucleus with inconsistent activity in the frontal lobe was observed. CONCLUSIONS: This study has demonstrated the feasibility of recording brain responses to rectal mechanical stimulation using fMRI in patients with FI, revealing activity in widespread areas of the brain involved in visceral sensory processing. The observed activity in the supplementary motor cortex and caudate nucleus, with relative paucity of activity in the frontal lobes, warrants investigation in future studies to determine whether aberrations in cerebral processing of rectal stimuli play a role in the pathogenesis of FI.

Cortical abnormalities in adults and adolescents with major depression based on brain scans from 20 cohorts worldwide in the ENIGMA Major Depressive Disorder Working Group.

The neuro-anatomical substrates of major depressive disorder (MDD) are still not well understood, despite many neuroimaging studies over the past few decades. Here we present the largest ever worldwide study by the ENIGMA (Enhancing Neuro Imaging Genetics through Meta-Analysis) Major Depressive Disorder Working Group on cortical structural alterations in MDD. Structural T1-weighted brain magnetic resonance imaging (MRI) scans from 2148 MDD patients and 7957 healthy controls were analysed with harmonized protocols at 20 sites around the world. To detect consistent effects of MDD and its modulators on cortical thickness and surface area estimates derived from MRI, statistical effects from sites were meta-analysed separately for adults and adolescents. Adults with MDD had thinner cortical gray matter than controls in the orbitofrontal cortex (OFC), anterior and posterior cingulate, insula and temporal lobes (Cohen's d effect sizes: -0.10 to -0.14). These effects were most pronounced in first episode and adult-onset patients (>21 years). Compared to matched controls, adolescents with MDD had lower total surface area (but no differences in cortical thickness) and regional reductions in frontal regions (medial OFC and superior frontal gyrus) and primary and higher-order visual, somatosensory and motor areas (d: -0.26 to -0.57). The strongest effects were found in recurrent adolescent patients. This highly powered global effort to identify consistent brain abnormalities showed widespread cortical alterations in MDD patients as compared to controls and suggests that MDD may impact brain structure in a highly dynamic way, with different patterns of alterations at different stages of life.

Episodic memory in depression: the unique contribution of the anterior caudate and hippocampus.

BACKGROUND: Learning and memory impairments in older adults with depression are linked to hippocampal atrophy. However, other subcortical regions may also be contributing to these deficits. We aimed to examine whether anterior caudate nucleus volume is significantly reduced in older adults with depression compared to controls; whether anterior caudate volume is associated with performance on tasks of episodic learning and memory, and if so, whether this association is independent of the effects of the hippocampus. METHOD: Eighty-four health-seeking participants meeting criteria for lifetime major depressive disorder (mean age = 64.2, s.d. = 9.1 years) and 27 never-depressed control participants (mean age = 63.9, s.d. = 8.0 years) underwent neuropsychological assessment including verbal episodic memory tests [Rey Auditory Verbal Learning Test and Logical Memory (WMS-III)]. Magnetic resonance imaging was conducted, from which subregions of the caudate nucleus were manually demarcated bilaterally and hippocampal volume was calculated using semi-automated methods. RESULTS: Depressed subjects had smaller right anterior caudate (RAC) (t = 2.3, p = 0.026) and poorer memory compared to controls (t = 2.5, p < 0.001). For depressed subjects only, smaller RAC was associated with poorer verbal memory (r = 0.3, p = 0.003) and older age (r = -0.46, p < 0.001). Multivariable regression showed that the RAC and hippocampus volume uniquely accounted for 5% and 3% of the variance in memory, respectively (ß = 0.25, t = 2.16, p = 0.033; ß = 0.19, t = 1.71, p = 0.091). CONCLUSIONS: In older people with depression, the anterior caudate nucleus and the hippocampus play independent roles in mediating memory. While future studies examining this structure should include larger sample sizes and adjust for multiple comparisons, these findings support the critical role of the striatum in depression.

Subcortical brain alterations in major depressive disorder: findings from the ENIGMA Major Depressive Disorder working group.

The pattern of structural brain alterations associated with major depressive disorder (MDD) remains unresolved. This is in part due to small sample sizes of neuroimaging studies resulting in limited statistical power, disease heterogeneity and the complex interactions between clinical characteristics and brain morphology. To address this, we meta-analyzed three-dimensional brain magnetic resonance imaging data from 1728 MDD patients and 7199 controls from 15 research samples worldwide, to identify subcortical brain volumes that robustly discriminate MDD patients from healthy controls. Relative to controls, patients had significantly lower hippocampal volumes (Cohen's d=-0.14, % difference=-1.24). This effect was driven by patients with recurrent MDD (Cohen's d=-0.17, % difference=-1.44), and we detected no differences between first episode patients and controls. Age of onset ⩽21 was associated with a smaller hippocampus (Cohen's d=-0.20, % difference=-1.85) and a trend toward smaller amygdala (Cohen's d=-0.11, % difference=-1.23) and larger lateral ventricles (Cohen's d=0.12, % difference=5.11). Symptom severity at study inclusion was not associated with any regional brain volumes. Sample characteristics such as mean age, proportion of antidepressant users and proportion of remitted patients, and methodological characteristics did not significantly moderate alterations in brain volumes in MDD. Samples with a higher proportion of antipsychotic medication users showed larger caudate volumes in MDD patients compared with controls. This currently largest worldwide effort to identify subcortical brain alterations showed robust smaller hippocampal volumes in MDD patients, moderated by age of onset and first episode versus recurrent episode status.

Neurodevelopmental sequelae associated with gray and white matter changes and their cellular basis: A comparison between Autism Spectrum Disorder, ADHD and dyslexia.

Many psychiatric diseases, such as major depression and schizophrenia, are accompanied by patterns of gray matter and white matter changes in the cortex that may be due to structural pathologies of synapses and their dendrites in the gray matter on the one hand and to pathologies in myelinating oligodendrocytes on the other. Here the possibility has been briefly examined that such a generalization might also hold for Autistic Spectrum Disorders (ASD). Evidence is presented that gray matter changes that accompany ASD may in fact reflect changes in synapses and subsequently of their dendrites, whereas those in the white matter reflect changes in myelination due to pathologies of oligodendrocytes. It is proposed that such structural pathologies during development provide a coherent biological model not only for the onset and course of ASD but also provide the basis for development and systematic evaluation of new treatment strategies.

Right external globus pallidus changes are associated with altered causal awareness in youth with depression.

Cognitive impairment is a functionally disabling feature of depression contributing to maladaptive decision-making, a loss of behavioral control and an increased disease burden. The ability to calculate the causal efficacy of ones actions in achieving specific goals is critical to normal decision-making and, in this study, we combined voxel-based morphometry (VBM), shape analysis and diffusion tensor tractography to investigate the relationship between cortical-basal ganglia structural integrity and such causal awareness in 43 young subjects with depression and 21 demographically similar healthy controls. Volumetric analysis determined a relationship between right pallidal size and sensitivity to the causal status of specific actions. More specifically, shape analysis identified dorsolateral surface vertices where an inward location was correlated with reduced levels of causal awareness. Probabilistic tractography revealed that affected parts of the pallidum were primarily connected with the striatum, dorsal thalamus and hippocampus. VBM did not reveal any whole-brain gray matter regions that correlated with causal awareness. We conclude that volumetric reduction within the indirect pathway involving the right dorsolateral pallidum is associated with reduced awareness of the causal efficacy of goal-directed actions in young depressed individuals. This causal awareness task allows for the identification of a functionally and biologically relevant subgroup to which more targeted cognitive interventions could be applied, potentially enhancing the long-term outcomes for these individuals.

Neuropsychological and functional outcomes in recent-onset major depression, bipolar disorder and schizophrenia-spectrum disorders: a longitudinal cohort study.

Functional disability is the lead contributor to burden of mental illness. Cognitive deficits frequently limit functional recovery, although whether changes in cognition and disability are longitudinally associated in recent-onset individuals remains unclear. Using a prospective, cohort design, 311 patients were recruited and assessed at baseline. One hundred and sixty-seven patients met eligibility criteria (M=21.5 years old, s.d.=4.8) and returned for follow-up (M=20.6 months later, s.d.=7.8). Two-hundred and thirty participants were included in the final analysis, comprising clinically stable patients with major depression (n=71), bipolar disorder (BD; n=61), schizophrenia-spectrum disorders (n=35) and 63 healthy controls. Neuropsychological functioning and self-rated functional disability were examined using mixed-design, repeated-measures analysis, across diagnoses and cognitive clusters, covarying for relevant confounds. Clinical, neuropsychological and functional changes did not differ between diagnoses (all P>0.05). Three reliable neuropsychological subgroups emerged through cluster analysis, characterized by psychomotor slowing, improved sustained attention, and improved verbal memory. Controlling for diagnosis and changes in residual symptoms, clusters with improved neuropsychological functioning observed greater reductions in functional disability than the psychomotor slowing cluster, which instead demonstrated a worsening in disability (P<0.01). Improved sustained attention was independently associated with greater likelihood of follow-up employment (P<0.01). Diagnosis of BD uniquely predicted both follow-up employment and independent living. Neuropsychological course appears to be independently predictive of subjective and objective functional outcomes. Importantly, cognitive phenotypes may reflect distinct pathophysiologies shared across major psychiatric conditions, and be ideal targets for personalized early intervention.

Stress and trauma: BDNF control of dendritic-spine formation and regression.

Chronic restraint stress leads to increases in brain derived neurotrophic factor (BDNF) mRNA and protein in some regions of the brain, e.g. the basal lateral amygdala (BLA) but decreases in other regions such as the CA3 region of the hippocampus and dendritic spine density increases or decreases in line with these changes in BDNF. Given the powerful influence that BDNF has on dendritic spine growth, these observations suggest that the fundamental reason for the direction and extent of changes in dendritic spine density in a particular region of the brain under stress is due to the changes in BDNF there. The most likely cause of these changes is provided by the stress initiated release of steroids, which readily enter neurons and alter gene expression, for example that of BDNF. Of particular interest is how glucocorticoids and mineralocorticoids tend to have opposite effects on BDNF gene expression offering the possibility that differences in the distribution of their receptors and of their downstream effects might provide a basis for the differential transcription of the BDNF genes. Alternatively, differences in the extent of methylation and acetylation in the epigenetic control of BDNF transcription are possible in different parts of the brain following stress. Although present evidence points to changes in BDNF transcription being the major causal agent for the changes in spine density in different parts of the brain following stress, steroids have significant effects on downstream pathways from the TrkB receptor once it is acted upon by BDNF, including those that modulate the density of dendritic spines. Finally, although glucocorticoids play a canonical role in determining BDNF modulation of dendritic spines, recent studies have shown a role for corticotrophin releasing factor (CRF) in this regard. There is considerable improvement in the extent of changes in spine size and density in rodents with forebrain specific knockout of CRF receptor 1 (CRFR1) even when the glucocorticoid pathways are left intact. It seems then that CRF does have a role to play in determining BDNF control of dendritic spines.

Microstructural white matter changes are correlated with the stage of psychiatric illness.

Microstructural white matter changes have been reported in the brains of patients across a range of psychiatric disorders. Evidence now demonstrates significant overlap in these regions in patients with affective and psychotic disorders, thus raising the possibility that these conditions share common neurobiological processes. If affective and psychotic disorders share these disruptions, it is unclear whether they occur early in the course or develop gradually with persistence or recurrence of illness. Utilisation of a clinical staging model, as an adjunct to traditional diagnostic practice, is a viable mechanism for measuring illness progression. It is particularly relevant in young people presenting early in their illness course. It also provides a suitable framework for determining the timing of emergent brain alterations, including disruptions of white matter tracts. Using diffusion tensor imaging, we investigated the integrity of white matter tracts in 74 patients with sub-syndromal psychiatric symptoms as well as in 69 patients diagnosed with established psychosis or affective disorder and contrasted these findings with those of 39 healthy controls. A significant disruption in white matter integrity was found in the left anterior corona radiata and in particular the anterior thalamic radiation for both the patients groups when separately contrasted with healthy controls. Our results suggest that patients with sub-syndromal symptoms exhibit discernable early white matter changes when compared with healthy control subjects and more significant disruptions are associated with clinical evidence of illness progression.

In vivo glutathione levels in young persons with bipolar disorder: a magnetic resonance spectroscopy study.

Oxidative stress has recently been reported to assume a significant role in the pathophysiology of bipolar disorder. Several studies have demonstrated the replenishment of glutathione (GSH) diminishes oxidative cellular damage and ameliorates depressive symptoms in this disorder. Whilst the mechanism by which GSH exerts any clinical effect is unknown it has been proposed that it involves the bolstering of antioxidant defences by increasing the bioavailability of GSH, which in turn reverses clinical symptoms of depression. Such a proposal is predicated on the implicit assumption that GSH is diminished in these patients prior to GSH supplementation. However hitherto no study has reported in vivo measures of GSH in patients with bipolar disorder. Using magnetic resonance spectroscopy we obtained in vivo measures of GSH in young people with bipolar disorder and contrasted these with matched healthy controls. Young people with bipolar disorder were found to have no diminution in baseline GSH concentration and, furthermore, no significant correlations were found between GSH and clinical scores of depression or mania. The results do not support the hypothesis that oxidative stress is involved in the primary pathophysiology of bipolar disorder.

A systematic review of functional magnetic resonance imaging and diffusion tensor imaging modalities used in presurgical planning of brain tumour resection.

Historically, brain tumour resection has relied upon standardised anatomical atlases and classical mapping techniques for successful resection. While these have provided adequate results in the past, the emergence of new technologies has heralded a wave of less invasive, patient-specific techniques for the mapping of brain function. Functional magnetic resonance imaging (fMRI) and, more recently, diffusion tensor imaging (DTI) are two such techniques. While fMRI is able to highlight localisation of function within the cortex, DTI represents the only technique able to elucidate white matter structures in vivo. Used in conjunction, both of these techniques provide important presurgical information for thorough preoperative planning, as well as intraoperatively via integration into frameless stereotactic neuronavigational systems. Together, these techniques show great promise for improved neurosurgical outcomes. While further research is required for more widespread clinical validity and acceptance, results from the literature provide a clear road map for future research and development to cement these techniques into the clinical setup of neurosurgical departments globally.

A systematic review of resting-state functional-MRI studies in major depression.

BACKGROUND: To evaluate the literature pertaining to the use of resting-state functional magnetic resonance imaging (fMRI) in Major Depression (MD). METHODS: A search for papers published in English was conducted using MedLine, Embase, PsycINFO, OvidSP, and ScienceDirect with the following words: resting state, depression, MRI, affective, and default-mode. RESULTS: The findings from 16 resting-state fMRI studies on MD are tabulated. Some common findings are discussed in further detail. CONCLUSION: The use of resting-state fMRI in MD research has yielded a number of significant findings that provide the basis for understanding the pathophysiology of depressive symptoms. Of particular note and deserving of further research are the roles of the cortico-limbic mood regulating circuit (MRC) and the interaction between task-positive and task-negative networks in MD. There is increasing interest in the use of resting-state fMRI in the study of psychiatric conditions, and continued improvement in technique and methodology will prove valuable in future research.

Distinct neurometabolic profiles are evident in the anterior cingulate of young people with major psychiatric disorders.

Currently, there are no validated neurobiological methods for distinguishing different pathophysiological pathways in young patients presenting in the early phases of major psychiatric disorders. Hence, treatments are delivered simply on the basis of their possible effects on nonspecific symptom constructs such as depression, cognitive change or psychotic symptoms. In this study, the ratios (relative to creatine) of key metabolites (N-acetyl aspartate, myoinositol, glutamate and glutathione) were measured with proton magnetic resonance spectroscopy ((1)H-MRS) within the anterior cingulate cortex of 88 young persons presenting with major mood or psychotic symptoms. We derived empirically (using a cluster analytical technique) three subgroups of subjects on the basis of their patterns of in vivo brain biochemistry. The three subgroups were distinguished (from each other) by all the four metabolites, in particular, glutathione and glutamate. By contrast, the groups could not be distinguished by differences in terms of other demographic, functional or clinical measures. We propose that this (1)H-MRS-based subclassification system could be used as the basis for much more specific tests of novel intervention strategies (notably, antioxidant and glutamatergic therapies) early in the course of major psychiatric disorders.

Making sense of neuroimaging in psychiatry.

OBJECTIVE: Neuroimaging of psychiatric disorders has increased exponentially in the last decade; however, much of the uptake thus far has been in the realm of research. We anticipate that clinical use of neuroimaging modalities in psychiatry will increase dramatically in the near future and suggest that clinicians need to be aware of the potential applications. METHOD: The authors conducted an extensive MEDLINE, EMBASE, PubMED and PsychInfo search of the published literature (1965-2007) using a variety of search terms to find relevant articles. Bibliographies of retrieved papers were further scrutinised for publications of interest, as were indices of books. Articles that reported clinically significant findings and research reports conducted using pertinent neuroimaging modalities were reviewed in detail. RESULTS: The review suggests that exciting neuroimaging advances are being made that have relevance to psychiatry. Novel neuroimaging applications with potential clinical utility are rapidly emerging and the accessibility and use of these technologies will increase in coming years. Clinically meaningful findings have begun to emerge in mood disorders, post-traumatic stress disorder, schizophrenia and dementia. Coupling multimodal imaging with genetics and pharmacotherapeutic studies will further assist in understanding the pathophysiology of neuropsychiatric disorders. CONCLUSION: It is important that clinicians understand the benefits and limitations of modern neuroimaging techniques and are also suitably equipped to appraise future developments. The use of neuroimaging in evaluating psychopathology is likely to impact upon the future nosology of psychiatric disorders, and assist in diagnosis and clinical management. The integrated use of neuroimaging in conjunction with clinical assessments promises to improve clinical care and markedly alter psychiatric practice.