Ketamine and Zinc: Treatment of Anorexia Nervosa Via Dual NMDA Receptor Modulation.

Anorexia nervosa is a disorder associated with serious adverse health outcomes, for which there is currently considerable treatment ineffectiveness. Characterised by restrictive eating behaviours, distorted body image perceptions and excessive physical activity, there is growing recognition anorexia nervosa is associated with underlying dysfunction in excitatory and inhibitory neurometabolite metabolism and signalling. This narrative review critically explores the role of N-methyl-D-aspartate receptor-mediated excitatory and inhibitory neurometabolite dysfunction in anorexia nervosa and its associated biomarkers. The existing magnetic resonance spectroscopy literature in anorexia nervosa is reviewed and we outline the brain region-specific neurometabolite changes that have been reported and their connection to anorexia nervosa psychopathology. Considering the proposed role of dysfunctional neurotransmission in anorexia nervosa, the potential utility of zinc supplementation and sub-anaesthetic doses of ketamine in normalising this is discussed with reference to previous research in anorexia nervosa and other neuropsychiatric conditions. The rationale for future research to investigate the combined use of low-dose ketamine and zinc supplementation to potentially extend the therapeutic benefits in anorexia nervosa is subsequently explored and promising biological markers for assessing and potentially predicting treatment response are outlined.

The effect of mindfulness training on resting-state networks in pre-adolescent children with sub-clinical anxiety related attention impairments.

Mindfulness training has been associated with improved attention and affect regulation in preadolescent children with anxiety related attention impairments, however little is known about the underlying neurobiology. This study sought to investigate the impact of mindfulness training on functional connectivity of attention and limbic brain networks in pre-adolescents. A total of 47 children with anxiety and/or attention issues (aged 9-11 years) participated in a 10-week mindfulness intervention. Anxiety and attention measures and resting-state fMRI were completed at pre- and post-intervention. Sustained attention was measured using the Conners Continuous Performance Test, while the anxiety levels were measured using the Spence Children's Anxiety Scale. Functional networks were estimated using independent-component analysis, and voxel-based analysis was used to determine the difference between the time-points to identify the effect of the intervention on the functional connectivity. There was a significant decrease in anxiety symptoms and improvement in attention scores following the intervention. From a network perspective, the results showed increased functional connectivity post intervention in the salience and fronto-parietal networks as well as the medial-inferior temporal component of the default mode network. Positive correlations were identified in the fronto-parietal network with Hit Response Time and the Spence Children's Anxiety Scale total and between the default mode network and Hit Response Time. A 10-week mindfulness intervention in children was associated with a reduction in anxiety related attention impairments, which corresponded with concomitant changes in functional connectivity.

Anorexia nervosa, zinc deficiency and the glutamate system: The ketamine option.

Anorexia nervosa (AN) is a severe, biological brain disorder with significant medical risks and a tenacious development over time. Unfortunately, few treatments show efficacy in people with AN although numerous therapies including pharmacological have been explored. Zinc deficiency has been implicated in AN and zinc is important in a large range of processes in the brain. In particular, it is an allosteric modulator of NMDA receptors - the maintenance of zinc levels within a normal, narrow range is essential for glutamatergic functioning. Chronic zinc deficiency increases neuronal stores of calcium and reduces direct modulation of NMDA receptors which collectively lead to overactivation and upregulation of NMDA receptors. This may facilitate pathologically high levels of glutamate, calcium influx and subsequent excitotoxicity, which can disrupt synaptogenesis and synaptic plasticity. While studies of zinc supplementation in AN have shown some promise, the efficacy of this treatment is limited. This may be due to AN illness chronicity and the significant changes already made, as well as a reduced potency of zinc to inhibit NMDA receptors in a pathological state. Thus, we propose that the safe (at low doses) yet more potent NMDA receptor antagonist, ketamine, may act to normalise a perturbed glutamatergic system and increase synaptogenesis in the short term. This 'kickstart' via ketamine could then allow zinc supplementation and other forms of treatment to enhance recovery in AN.

Mental training affects electrophysiological markers of attention resource allocation in healthy older adults.

Aging is associated with a decline in performance and speed of attentional processing. Mindfulness has been shown to enhance attentional performance, however evidence of this is lacking in aging cohorts. A longitudinal RCT was conducted to examine the effect of mindfulness training on attentional performance in healthy older adults (n = 49) together with an active control computer-based attention training group (n = 30). While both groups displayed decreased N2 amplitudes at frontal and central regions during an auditory oddball task after training, only the mindfulness group showed reductions in frontal N2 and P3 latency. These results suggest that programs targeting sustained attention may result in efficient allocation of attentional resources in older adults. In particular, mindfulness may enhance the speed of attentional processes which are known to decline in aging, thereby providing benefits against age-related cognitive decline.

Mismatch negativity in bipolar disorder: A neurophysiological biomarker of intermediate effect?

The event-related potential, mismatch negativity (MMN), has been touted as a robust and specific neurophysiological biomarker of schizophrenia. Earlier studies often included bipolar disorder (BD) as a clinical comparator and reported that MMN was significantly impaired only in schizophrenia. However, with the increasing number of MMN studies of BD (with larger sample sizes), the literature is now providing somewhat consistent evidence of this biomarker also being perturbed in BD, albeit to a lesser degree than that observed in schizophrenia. Indeed, two meta-analyses have now shown that the effect sizes in BD samples suggest a moderate impairment in MMN, compared to the large effect sizes shown in schizophrenia. Pharmacologically, MMN is an extremely useful non-invasive probe of glutamatergic (more specifically, N-methyl-d-aspartate [NMDA] receptor) disturbances and this system has been implicated in the pathophysiology of both schizophrenia and BD. Therefore, it may be best to conceptualize/utilize MMN as an index of a psychopathology that is shared across psychotic and related disorders, rather than being a diagnosis-specific biomarker. More research is needed, particularly longitudinal designs including studies that assess MMN over an individual's life course and then examine NMDA receptor expression/binding post-mortem. At this point and despite a disproportionate amount of research, the current evidence suggests that with respect to BD, MMN is a neurophysiological biomarker of intermediate effect. With replication and validation of this effect, MMN may prove to be an important indicator of a common psychopathology shared by a significant proportion of individuals with schizophrenia and bipolar spectrum illnesses.

Youth depression alleviation: the Fish Oil Youth Depression Study (YoDA-F): A randomized, double-blind, placebo-controlled treatment trial.

AIM: US authorities have recommended 'black-box' warnings for antidepressants because of the increased risk of suicidality for individuals up to age 25. There is thus a clinical and ethical imperative to provide effective treatment for youth depression with an acceptable risk-benefit balance. Long-chain omega-3 polyunsaturated fatty acids (PUFAs) play an important role in a range of physiological processes in living organisms. Supplementation with omega-3 PUFAs has been shown to have a range of beneficial effects on both physical and mental health, and results of previous trials suggest that omega-3 PUFAs may be a safe and effective treatment for depression. However, conclusions from these trials have been limited by their relatively small sample sizes. METHODS: This trial will test the effectiveness of a 12-week parallel group, double-blind, randomized, placebo-controlled trial of 1.4 g day(-1) omega-3 PUFAs in help seeking 15- to 25-year-olds (N = 400) presenting with major depressive disorder. The primary hypothesis is that young people will show greater improvement of depressive symptoms after 12 weeks of treatment with omega-3 PUFAs plus cognitive behavioural case management compared with treatment with placebo plus cognitive behavioural case management. CONCLUSION: Because of using a large sample, results from this study will provide the strongest evidence to date to inform the use of omega-3 PUFAs as first-line therapy in young people presenting with major depressive disorder. The study also heralds an important step towards indicated prevention of persistent depression, which may reduce the burden, stigmatization, disability and economic consequences of this disorder.

The effect of 12-wk ω-3 fatty acid supplementation on in vivo thalamus glutathione concentration in patients "at risk" for major depression.

OBJECTIVES: As life expectancy increases, the need to prevent major health disorders is clear. Depressive symptoms are common in older adults and are associated with cognitive decline and greater risk for transitioning to major depression. Oxidative stress may be implicated in the pathophysiology of major depression and can be measured in vivo using proton magnetic resonance spectroscopy via the neurometabolite glutathione (GSH). Evidence suggests ω-3 fatty acid (FA) supplementation may prevent depression and directly affect GSH concentration. The aim of this study was to examine the effect of ω-3 FA supplementation on in vivo GSH concentration in older adults at risk for depression. METHODS: Fifty-one older adults at risk for depression were randomized to receive either four 1000-mg ω-3 FA supplements daily (containing eicosapentaenoic acid 1200 mg plus docosahexaenoic acid 800 mg) or placebo (four 1000-mg paraffin oil placebo capsules daily) for 12 wk. Participants underwent magnetic resonance spectroscopy, as well as medical, neuropsychological, and self-report assessments at baseline and after 12 wk of supplementation. GSH was measured in the thalamus and calculated as a ratio to creatine. Depressive symptoms were measured using the Patient Health Questionnaire. RESULTS: Compared with the group given the ω-3 FA supplements, the placebo group had greater change in the GSH-to-creatine ratio in the thalamus (t = 2.00; P = 0.049) after the 12 wk intervention. This increase was in turn associated with a worsening of depressive symptoms (r = 0.43; P = 0.043). CONCLUSIONS: Depressive symptom severity in older adults appears to be associated with increased brain levels of GSH, a key marker of oxidative stress. Importantly, ω-3 FA supplementation may attenuate oxidative stress mechanisms, thereby offering benefits for depression prevention.

A systematic review and meta-analysis of proton magnetic resonance spectroscopy and mismatch negativity in bipolar disorder.

Aberrant glutamate neurotransmission has been implicated in the pathophysiology of bipolar disorder with accumulating evidence from imaging, post-mortem and pathology studies. Studies investigating in vivo changes to the glutamatergic system have not been as consistent and warrant clarification. Studies utilizing proton-magnetic resonance spectroscopy ((1)H-MRS) have reported increased levels of combined glutamate and glutamine ("Glx"), which have been linked to impairments in N-methyl-d-aspartate (NMDA) receptor function. Similarly, neurophysiological studies utilising mismatch negativity (MMN) as an index of NMDA receptor function, have reported impairments in bipolar disorder. Here, we provide a systematic review of the literature in regards to the concentration of Glx and the magnitude of MMN in bipolar disorder. Separate meta-analyses revealed that bipolar disorder was associated with increased Glx concentration and decreased MMN-both measured frontally. The current findings corroborate previous evidence indicating that bipolar disorder is characterized by a perturbed frontal glutamate system. These observed changes in bipolar disorder might manifest as impairments in neuronal-glial interactions that lead to disrupted neuronal output and ultimately result in the characteristic neurocognitive sequelae associated with this disorder.

Sex differences in brain maturation as measured using event-related potentials.

Little is known about how sex influences functional brain maturation. The current study investigated sex differences in the maturation of event-related potential (ERP) amplitudes during an auditory oddball task (N = 170; age = 6-17 years). Performance improved with age. N200 amplitude declined with age: parietal sites showed earlier development than temporal and frontal locations. Girls showed greater bilateral frontal P300 amplitude development, approaching the higher values observed in boys during childhood. After controlling for age, right frontal P300 amplitude was associated with reaction time in girls. The findings demonstrate sex differences in ERP maturation in line with behavioral and neuroimaging studies.

Neurophysiological biomarkers support bipolar-spectrum disorders within psychosis cluster.

BACKGROUND: Mismatch negativity (MMN) and P3a are event-related potentials that index deviance detection and the orienting response, respectively. We have previously shown that the MMN/P3a complex is impaired in patients with schizophrenia and affective spectrum psychoses, which suggests that it may index a common pathophysiology and argues against the purported specificity in schizophrenia. Further research is warranted to determine whether patients with bipolar-spectrum disorders show similar impairments in these biomarkers. METHODS: We assessed patients aged 15-30 years with early schizophrenia-spectrum disorders (schizophrenia, schizoaffective disorder, schizophreniform disorder), early bipolar-spectrum disorders (bipolar I or II, with and without psychotic features) and healthy, matched controls. We acquired MMN/P3a amplitudes during a 2-tone, auditory paradigm with 8% duration deviants. Clinical, psychosocial and neuro psychological assessments were also undertaken. RESULTS: We included 20 patients with schizophrenia-spectrum disorders, 20 with bipolar-spectrum disorders and 20 controls in our study. Both patient groups showed significantly reduced frontocentral MMN and central P3a amplitudes. The schizophrenia-spectrum group had additional impairments in left temporal MMN and frontal P3a. Both patient groups performed worse than controls across psychosocial and clinical measures; however, only the schizophrenia-spectrum group performed significantly worse than controls for cognitive measures. Correlational analyses between patient groups revealed associations between frontocentral or left temporal MMN and psychiatric symptomatology or quality of life measures. LIMITATIONS: Limitations to our study include the modest sample size and the lack of control with regards to the effects of other (i.e., nonantipsychotic) psychotropic medications. CONCLUSION: Compared with patients in early stages of schizophrenia-spectrum disorders, those in the early stages of bipolar-spectrum disorders are similarly impaired in established biomarkers for schizophrenia. These findings support a shared diathesis model for psychotic and bipolar disorders. Furthermore, MMN/P3a may be a biomarker for a broader pathophysiology that overlaps traditional diagnostic clusters.

Alterations in theta activity associated with novelty and routinization processing in ADHD.

OBJECTIVE: Novelty and routinization-related information processing disturbances were examined in adolescent males with ADHD using an oddball paradigm and electrophysiological measurement of theta (4-7Hz) activity. METHODS: Fifty-four unmedicated adolescent males (12-18years) with Attention Deficit Hyperactivity Disorder (ADHD) and matched controls performed an auditory oddball task. Theta activity was sub-averaged, and Fourier Integrals with simultaneous measurement of electrodermal activity (EDA) was used to index response to stimulus novelty and routinization. RESULTS: ADHD participants showed an overall increase in theta activity to both novel and routine stimuli relative to controls. While controls showed increased theta activity in response to novel compared to routine targets across the brain, ADHD participants did not show this novelty-related increase in theta activity in the right anterior/frontal brain. CONCLUSIONS: The findings of this study are consistent with disturbances in theta activity and the brain substrates of novelty relative to routinization-related processing in ADHD. SIGNIFICANCE: These findings show that there are distinct alterations in theta activity related to stimulus novelty and routinization during an auditory oddball task in ADHD, and they highlight the value of using an event-related approach to elucidate the neural substrates of stimulus processing in ADHD.

Event-related wave activity in the EEG provides new marker of ADHD.

OBJECTIVE: This study examines the utility of new measures of event-related spatio-temporal waves in the EEG as a marker of ADHD, previously shown to be closely related to the P3 ERP in an adult sample. METHODS: Wave activity in the EEG was assessed during both an auditory Oddball and a visual continuous performance task (CPT) for an ADHD group ranging in age from 6 to 18 years and comprising mostly Combined and Inattentive subtypes, and for an age and gender matched control group. RESULTS: The ADHD subjects had less wave activity at low frequencies ( approximately 1 Hz) during both tasks. For auditory Oddball targets, this effect was shown to be related to smaller P3 ERP amplitudes. During CPT, the approximately 1 Hz wave activity in the ADHD subjects was inversely related to clinical and behavioral measures of hyperactivity and impulsivity. CPT wave activity at approximately 1 Hz was seen to "normalise" following treatment with stimulant medication. CONCLUSIONS: The results identify a deficit in low frequency wave activity as a new marker for ADHD associated with levels of hyperactivity and impulsivity. SIGNIFICANCE: The marker is evident across a range of tasks and may be specific to ADHD. While lower approximately 1 Hz activity partly accounts for reduced P3 ERPs in ADHD, the effect also arises for tasks that do not elicit a P3. Deficits in behavioral inhibition are hypothesized to arise from underlying dysregulation of cortical inhibition.

An integrative approach to determine the best behavioral and biological markers of methylphenidate.

AIMS: To distinguish the most sensitive markers of methylphenidate (MPH) effects on behavior and underlying biology using an integrated cognitive and brain function test battery. METHODS: A randomized placebo-controlled trial with 32 healthy adult males. Subjects were tested on MPH doses across 18 sessions with subjective mood, objective behavioral and biological endpoints. From a computerized battery of tests, behavioral measures were cognitive performance scores, while biological measures of brain function included electroencephalographs (EEG) and event-related potentials (ERPs) with complementary measures of autonomic arousal. Using mixed modeling analyses; we determined which measures were most affected by MPH dose and correlation analyses determined the associations among them. RESULTS: MPH dose had the most pronounced effect on cognitive performance (sustained attention/vigilance), baseline autonomic arousal (heart rate, blood pressure) and baseline brain activity (EEG theta power). The faster reaction time, reduced errors, increased autonomic arousal and reductions in theta showed strong to moderate inter-correlations. MPH least affected subjective mood measures and early sensory ERP components. DISCUSSION: These findings suggest that MPH increases cortical and autonomic arousal, facilitating vigilance. The combination of behavioral and biological measures may provide an objective set of markers of MPH response. INTEGRATIVE SIGNIFICANCE: This approach has provided additional insight into the mechanism of the stimulant medication, MPH, which would not be achieved by using such measures in isolation.