Research report
Reduced long distance gamma (28–48 Hz) coherence in euthymic patients with bipolar disorder

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Abstract

Background

EEG coherence represents the brain's functional connectivity. Synchronous neural gamma oscillations are critical for cortico-cortical communication and large-scale integration of distributed sets of neurons. We investigated long distance gamma (28–48 Hz) coherence in bipolar disorder.

Methods

Sensory evoked coherence (EC) and event related coherence (ERC) values for the gamma frequency band during simple light stimulation and visual odd-ball paradigm was assessed in 20 drug-free euthymic bipolar patients in comparison to healthy controls. Groups were compared for the coherence values of the left (F3-T3, F3-TP7, F3-P3, F3-O1) and right (F4-T4, F4-TP8, F4-P4, F4-O2) intra-hemispheric electrode pairs by means of a repeated measure analysis of variance (ANOVA) and t-tests.

Results

Patients showed significantly lower gamma coherence values in response to target stimuli than the healthy controls between left and right fronto-temporal, as well as between frontal and temporo-parietal electrode pairs. Coherence values for the non-target stimuli were significantly lower in the patients than the healthy controls between frontal and temporo-parietal regions on both right and left sides. EP coherence values did not differ significantly between the groups.

Limitations

A relatively small sample size is the major limitation of the study.

Conclusions

Bipolar patients present disturbance in functional long-range connectivity between the frontal and temporal as well as temporo-parietal brain structures during a cognitive paradigm requiring attention and immediate recall. The location of the connectivity disturbance corresponds to the underlying neurobiology of executive function, memory and attention impairments in bipolar disorder and raises the question of whether gamma coherence reduction may be a candidate biomarker for bipolar disorder.

Introduction

The utilization of the concept and methods of oscillatory brain dynamics in neuropsychiatric disorders has increased rapidly during the last decade (Başar and Güntekin, 2008, Uhlhaas et al., 2008, Herrmann et al., 2010, O'Donnell et al., 2004, Spencer et al., 2008). The aim of the present study was to explore long distance gamma coherence in euthymic drug-free patients with bipolar disorder. The research objective was informed by recent findings by our group, pointing to long distance connectivity dysfunction in mania (Özerdem et al., 2008, Özerdem et al., 2010).

Bipolar disorder is a chronic illness with a relapsing and remitting course. Relapses are manic or depressive in nature. It is one of the most debilitating illnesses worldwide (Murray and Lopez, 1996), and has a prevalence of at least 1%. Mania is the core feature of the illness which gives rise to the definite diagnosis (American Psychiatric Association, 1994). Manic state is characterized by increased energy and motor activity, decreased need for sleep, distractibility with a strong involvement of pleasure seeking and impulsive behavior. Manic patients also display signs of dysfunction in attentional measures, complex processing and memory as well as emotional processing (Quraishi and Frangou, 2002). Depressed mood, loss of or decrease in interest, decreased energy, psychomotor retardation or agitation, sleep and appetite disturbances, decreased self esteem, thoughts of guilt, suicidal thoughts, attentional and memory deficits characterize depressive episodes (American Psychiatric Association, 1994). Patients show impairment in verbal recall, fine motor skills (Malhi et al., 2007) and disturbance of sustained attention (Holmes et al., 2008). Having an acute episode of mania or depression is suggested to give way to damage to learning and memory systems (Bearden et al., 2001). Euthymia is the symptom free, well being state of bipolar disorder. However, a recent meta-analysis revealed deficits in response inhibition set shifting, executive function, verbal memory and sustained attention, processing speed, visual memory and verbal fluency in euthymia (Bora et al., 2009). Based on these findings, Bora et al. (2009) state that the cognitive endophenotype of bipolar disorder involves fronto-temporal and fronto-limbic related cognitive impairments.

Bipolar disorder type I (BPI) is particularly associated with a poor clinical and functional outcome, and represents a serious economic burden (Baldessarini and Tondo, 2003). The risk of suicide is high in bipolar disorder (Valtonen et al., 2005). Frequent misdiagnosis and late diagnosis of the disorder are the main reasons for the poor prognosis in bipolar disorder (Bowden, 2001, Bowden, 2005), leading to delays in the initiation of appropriate treatment. The recent research agenda for the Diagnostic and Statistical Manual of Mental Disorders (DSM-V, 5th Edition), emphasizes a need to translate basic and clinical neuroscience research findings into a new classification system for all psychiatric disorders, based upon pathophysiologic and etiological processes (Phillips and Vieta, 2007).

Bipolar disorder is a complex illness challenging discovery of the underlying mechanisms. The identification of endophenotypes (Thaker, 2008) is an important strategy, recently developed to facilitate identification of the neurobiological and genetic underpinnings of this disorder. With regard to cognitive impairments, response inhibition, set shifting, verbal memory and target detection impairments are considered to be potential candidate endophenotypes for bipolar disorder (Bora et al., 2009). A first step toward developing an endophenotype is the discovery of a marker that uniquely identifies the disorder.

We have recently reported significantly reduced long distance gamma coherence in response to visual odd-ball paradigm in manic states (Özerdem et al., 2010), representing disrupted functional fronto-temporal connectivity in mania. The finding followed a previous report of increased occipital beta activity in manic states (Özerdem et al., 2008), which was suggested to occur as a compensation to a presumed disrupted connectivity in the brain's integrative functioning. Both findings were considered to involve insufficient GABA transmission in bipolar disorder. In search of the underlying pathophysiology of the illness, we have previously studied oscillatory responses in drug-free euthymic bipolar patients and reported abnormally increased left frontal delta in response to visual odd-ball paradigm, which reduced after six weeks of valproate monotherapy (Özerdem et al., 2008).

In one of the very few studies addressing neural synchronization in bipolar disorder, patients in the manic or mixed state were shown to have deficits in auditory EEG synchronization in beta (20 Hz) and gamma (30, 40, and 50 Hz) range activity during click entrainment paradigm (O'Donnell et al., 2004). The degree of resting state long-range synchrony was found to be significantly reduced in manic patients compared to healthy controls in all frequency bands (Bhattacharya, 2001), whereas euthymic medicated patients displayed increased delta and decreased beta synchronization in the frontal region (Chen et al., 2008). Spencer et al. (2008) reported significantly reduced phase locking and reduced evoked power at 30 and 40 Hz stimulation as well as at 40-Hz harmonic of the 20-Hz auditory steady-state responses in first episode schizophrenia and affective psychosis patients compared to healthy controls. Finally, a recent study reported gamma oscillation decreases in the frontal regions of a mixed population of depressed and euthymic medicated patients with bipolar disorder in response to negative emotion context (Lee et al., 2010). Despite assessment of heterogeneous patient populations in different states of illness and different tasks and analysis methods applied in these studies, synchronization deficits in bipolar disorder seem to localize in the frontal and temporal regions and to be dominated by gamma and beta band deficits. The corresponding neurotransmitter disturbance was thought to be GABAergic (O'Donnell et al., 2004). Taken together, these findings can be accounted for the neurocognitive deficits in bipolar disorder.

EEG coherence describes the coupling of, or relationship between, signals in a given frequency band. Varying degrees of spatial coherence occur over long distances as parallel processing (Başar, 1980, Miltner et al., 1999, Schürmann et al., 2000). EEG coherence is considered to be an important large scale measure of functional relationships or synchronized functioning between pairs of cortical regions, and therefore represents the brain's functional connectivity (Nunez, 1997, Lopes da Silva et al., 1980, Petsche and Etlinger, 1998, Rappelsberger et al., 1982). Synchronous neural gamma oscillations are critical for cortico-cortical communication and the large-scale integration of distributed sets of neurons for integrated cognitive functioning (Rodriguez et al., 1999). Human studies reported stimulus specific gamma or gamma/beta synchronization over several centimeters during attentional and memory tasks (Tallon-Baudry et al., 2001). Coherence analysis has seldom been studied in neuropsychiatric disorders, nevertheless, presenting key findings in relation to the underlying functional pathophysiology in both bipolar disorder and Alzheimer's disease (Özerdem et al., 2010, Güntekin et al., 2008, Başar et al., 2010).

Since synchronous neural gamma oscillatory responses are required for integrative functioning of the brain, and as abnormal neuronal synchronization may contribute to deficits in cognitive and affective integration, such pathology as bipolar disorder with deficits in neurocognition and mood regulation might be expected to present disruption in gamma coherence especially between frontal and other intra-hemispheric structures. Assessment of unmedicated patients in euthymic state can provide a good opportunity to explore the underlying pathology of bipolar disorder since the condition is not confounded by any mood or behavioral symptoms and the previously shown possible medication effect on oscillatory responses (Özerdem et al., 2008, Özerdem et al., 2010), is eliminated. No study up to date has assessed long distance gamma coherence in such a homogeneous group of patients with bipolar disorder. It is also worth mentioning that assessment of both sensory evoked and event related (cognitive) coherence is important given the difference between the two measurements. The evoked coherence mostly reflects the augmentation or strengthening of links between various neural networks upon application of pure sensory signals, whereas the event related coherence reflects the strengthening of links (or neural connections) of neural networks upon stimulation by a sensory signal loaded with a cognitive task. Accordingly, upon application of a signal loaded with cognitive task (in this case the odd-ball paradigm) most possibly extended neural assemblies are activated; in turn, a recorded increase of coherence in a given frequency channel reflects the strengthening of links and amplification of electrical signal flow between the brain areas under examination.

Based on previous findings, the present study had two inter-related exploratory goals: 1. how can evoked and event related coherences serve in finding physiological and/or functional changes in the brain in bipolar disorder; 2. as gamma oscillations are thought to be linked to GABA/glutamate system (Gray and McCormick, 1996, Whittington et al., 1995), can the results open a new avenue to understand the interplay between neurotransmitters and oscillations, and thus future understanding of the basic mechanisms underlying the dysfunctional cognitive networks in bipolar disorder?

Section snippets

Participants

20 (6 male, and 14 female) DSM-IV (Diagnostic and Statistical Manual of Psychiatric Disorders-fourth edition) (American Psychiatric Association, 1994), bipolar I (n = 18) and II (n = 2) drug-free euthymic patients and 20 sex-matched, healthy controls were enrolled in the study. The study was approved by the local Ethics Committee for Clinical Trials at Bakirkoy Research and Training Hospital for Psychiatry and Neurology, Istanbul, Turkey. All participants provided written informed consent. Patients

Clinical characteristics

A summary of the clinical characteristics can be found in Table 1. Female and male participants were equally distributed in both patient and control groups (female/male: 14/6). Patients had a significantly higher mean age (32.15 ± 5.74; range 24.00–44.00 years) compared to healthy controls (27.60 ± 7.54; range: 20.00–41.00 years) (t: 2.147; p: 0.038). Mean years of education in the patient group (12.00 ± 3.45 range: 5.00–17.00 years) was significantly lower than that of the controls (14.35 ± 2.01; range:

What does the coherence change mean?

The present study examined the cortico-cortical connectivity in response to visual odd-ball paradigm in a group of drug-free euthymic patients with bipolar disorder in comparison to healthy controls, by measuring sensory and event related coherence by means of sensory visual stimulation and a visual odd-ball paradigm. The patients showed bilaterally diminished long distance gamma coherence between frontal and temporal as well as frontal and temporo-parietal regions compared to healthy controls.

Role of the funding source

Funding for this study was provided by an unrestricted research grant by Istanbul Kültür University; Istanbul Kültür University had no further role in study design; in the collection, analysis and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.

Conflict of interest

Ayşegül Özerdem has been on the advisory boards of pharma companies AstraZeneca, Janssen-Cilag, Eli-Lilly BMS, EGIS, GSK, Servier, Shering Plaugh, TEVA; has been a speaker for AstraZeneca, Eli-Lilly, BMS, Janssen-Cilag, EGIS, Sanofi-Aventis, GSK.

All other authors declare that they have no conflicts of interest.

Acknowledgement

The authors would like to thank E. Timucin Oral, MD for his contributions in bringing the two institutions (Istanbul Kültür University Brain Dynamics, Cognition, and Complex Systems Research Center, and Bakirkoy Research and Training Hospital for Psychiatry and Neurology) together for a long term collaboration.

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