Mismatch negativity/P3a complex in young people with psychiatric disorders : a cluster analysis

Background: We have recently shown that the event-related potential biomarkers, mismatch negativity (MMN) and P3a, are similarly impaired in young patients with schizophrenia- and affective-spectrum psychoses as well as those with bipolar disorder. A data driven approach may help to further elucidate novel patterns of MMN/P3a amplitudes that characterise distinct subgroups in patients with emerging psychiatric disorders. Methods: Eighty seven outpatients (16 to 30 years) were assessed: 19 diagnosed with a depressive disorder; 26 with a bipolar disorder; and 42 with a psychotic disorder. The MMN/P3a complex was elicited using a two-tone passive auditory oddball paradigm with duration deviant tones. Hierarchical cluster analysis utilising frontal, central and temporal neurophysiological variables was conducted. Results: Three clusters were determined: the 'globally impaired' cluster (n = 53) displayed reduced frontal and temporal MMN as well as reduced central P3a amplitudes; the 'largest frontal MMN' cluster (n = 17) were distinguished by increased frontal MMN amplitudes and the 'largest temporal MMN' cluster (n = 17) was characterised by increases in temporal MMN only. Notably, 55% of those in the globally impaired cluster were diagnosed with schizophrenia-spectrum disorder, whereas the three patient subgroups were equally represented in the remaining two clusters. The three cluster-groups did not differ in their current symptomatology; however, the globally impaired cluster was the most neuropsychologically impaired, compared with controls. Conclusions: These findings suggest that in emerging psychiatric disorders there are distinct MMN/P3a profiles of patient subgroups independent of current symptomatology. Schizophrenia-spectrum patients tended to show the most global impairments in this neurophysiological complex. Two other subgroups of patients were found to have neurophysiological profiles suggestive of quite different neurobiological (and hence, treatment) implications

Reconceptualising neurophysiological biomarkers of schizophrenia: an investigation of the MMN/P3a complex in early stage psychiatric disorders

This thesis investigated two established neurophysiological biomarkers of schizophrenia: mismatch negativity (MMN) and P3a; purported indices of the deviance detection and orienting response, respectively. In light of recent interest into a shared diathesis model between schizophrenia- and affective-spectrum disorders, this thesis evaluated the utility of MMN/P3a in informing the underlying neurobiology of early stages of schizophrenia- and affective-spectrum disorders. Despite differences in the composition of schizophrenia- and affective-spectrum subgroups, the first two studies showed that MMN/P3a was similarly impaired in the two diagnostic spectrums, with the schizophrenia-spectrum displaying more severe/widespread impairments. The third study utilised a data-driven method and determined three clusters with distinct patterns of MMN/P3a amplitudes among patients with emerging schizophrenia- and affective-spectrum disorders. Critically, about half of the cluster with the greatest neurophysiological impairments consisted of schizophrenia-spectrum patients. The last study explored the stability of MMN/P3a over time and its value in predicting functional outcomes in schizophrenia- and affective-spectrum patients. This study showed that MMN impairments worsen over time, suggestive of ongoing pathophysiological processes. Additionally, greater deficits in MMN amplitudes at baseline were associated with the most severe levels of later disability. In conclusion, this work has been a substantial contribution to the somewhat limited literature on MMN and P3a in early psychotic (and related) disorders. Critically, this thesis supports a re-conceptualisation of the proposed neurophysiological biomarkers of schizophrenia by demonstrating a broader application of MMN and P3a (in early schizophrenia- and affective-spectrum disorders). Accordingly, these studies also provide neurophysiological evidence of a shared diathesis between schizophrenia- and bipolar-spectrum disorders

An update on adjunctive treatment options for bipolar disorder

Objectives: Bipolar disorder is a complex illness often requiring combinations of therapies to successfully treat symptoms. In recent years, there have been significant advancements in a number of therapies for bipolar disorder. It is therefore timely to provide an overview of current adjunctive therapeutic options to help treating clinicians to inform their patients and work towards optimal outcomes. Methods: Publications were identified from PubMed searches on bipolar disorder and pharmacotherapy, nutraceuticals, hormone therapy, psychoeducation, interpersonal and social rhythm therapy, cognitive remediation, mindfulness, e-Health and brain stimulation techniques. Relevant articles in these areas were selected for further review. This paper provides a narrative review of adjunctive treatment options and is not a systematic review of the literature. Results: A number of pharmacotherapeutic, psychological and neuromodulation treatment options are available. These have varying efficacy but all have shown benefit to people with bipolar disorder. Due to the complex nature of treating the disorder, combination treatments are often required. Adjunctive treatments to traditional pharmacological and psychological therapies are proving useful in closing the gap between initial symptom remission and full functional recovery. Conclusions: Given that response to monotherapy is often inadequate, combination regimens for bipolar disorder are typical. Correspondingly, psychiatric research is working towards a better understanding of the disorder's underlying biology. Therefore, treatment options are changing and adjunctive therapies are being increasingly recognized as providing significant tools to improve patient outcomes. Towards this end, this paper provides an overview of novel treatments that may improve clinical outcomes for people with bipolar disorder

Lower In vivo Myo-Inositol in the Anterior Cingulate Cortex Correlates with Delayed Melatonin Rhythms in Young Persons with Depression

Myo-inositol, a second messenger glucose isomer and glial marker, is potentiated by melatonin. In addition to common abnormalities in melatonin regulation, depressive disorders have been associated with reduced myo-inositol in frontal structures. This study examined associations between myo-inositol in the anterior cingulate cortex and the timing of evening melatonin release. Forty young persons with unipolar depression were recruited from specialized mental health services (20.3 ± 3.8 years old). Healthy controls were recruited from the community (21.7 ± 2.6 years old). The timing of dim light melatonin onset (DLMO) was estimated using salivary melatonin sampling. Myo-inositol concentrations (MI/CrPCr ratio) in the anterior cingulate cortex were obtained using proton magnetic resonance spectroscopy. After controlling for age, sex, and CrPCr concentration the depression group had significantly lower MI/CrPCr ratios than healthy controls [F(4, 75) = 11.4, p = 0.001]. In the depression group, later DLMO correlated with lower MI/CrPCr ratio (r = −0.48, p = 0.014). These findings suggest that neurochemical changes in the frontal cortex are associated with circadian disruptions in young persons with depression

Investigating high- and low-frequency neuro-cardiac-guided TMS for probing the frontal vagal pathway

BACKGROUND: Investigating approaches for determining a functionally meaningful dorsolateral prefrontal cortex (DLPFC) stimulation site is imperative for optimising repetitive transcranial magnetic stimulation (rTMS) response rates for treatment-resistant depression. One proposed approach is neuro-cardiac-guided rTMS (NCG-TMS) in which high frequency rTMS is applied to the DLPFC to determine the site of greatest heart rate deceleration. This site is thought to index a frontal-vagal autonomic pathway that intersects a key pathway believed to underlie rTMS response. OBJECTIVE: We aimed to independently replicate previous findings of high-frequency NCG-TMS and extend it to evaluate the use of low-frequency rTMS for NCG-TMS. METHODS: Twenty healthy participants (13 female; aged 38.6 ± 13.9) underwent NCG-TMS on frontal, fronto-central (active) and central (control) sites. For high-frequency NCG-TMS, three 5 s trains of 10 Hz were provided at each left hemisphere site. For low-frequency NCG-TMS, 60 s trains of 1 Hz were applied to left and right hemispheres and heart rate and heart rate variability outcome measures were analysed. RESULTS: For high-frequency NCG-TMS, heart rate deceleration was observed at the left frontal compared with the central site. For low-frequency NCG-TMS, accelerated heart rate was found at the right frontal compared with central sites. No other site differences were observed. CONCLUSION: Opposite patterns of heart rate activity were found for high- and low-frequency NCG-TMS. The high-frequency NCG-TMS data replicate previous findings and support further investigations on the clinical utility of NCG-TMS for optimising rTMS site localisation. Further work assessing the value of low-frequency NCG-TMS for rTMS site localisation is warranted

Profile of standardised mean amplitude values (with standard error bars) for mismatch negativity (MMN) and P3a for the ‘globally impaired’ (red), ‘largest frontal MMN’ (blue) and ‘largest temporal MMN’ (green) cluster groups.

<p>Event-related potential mean amplitudes (µV) were standardised and corrected (for consistency in polarity between variables) so that positive values reflect increased amplitudes.</p

Cross-tabulation of cluster by medication category; Note: the ‘other psychotropic’ medications category includes benzodiazepines or stimulants.

<p>Cross-tabulation of cluster by medication category; Note: the ‘other psychotropic’ medications category includes benzodiazepines or stimulants.</p

Grand average event-related potentials for the ‘globally impaired’ (red), ‘largest frontal MMN (blue)’, ‘largest temporal MMN’ (green) cluster and control (black) groups at (from top to bottom) frontal (Fz), central (Cz) and left temporal (M1) sites.

<p><i>Note</i>: M1 waveforms are reversed in polarity due to the nose-referenced recording.</p