Results indicate that resting state EEG frequency abnormalities are evident in schizophrenia patients and their biological relatives but are largely absent in bipolar disorder patients and their biological relatives. High-frequency resting state EEG abnormalities may serve as an indicator of genetic liability specific to schizophrenia (ie, endophenotype). Relatives of schizophrenia patients exhibited more beta and gamma activity over frontal brain regions than nonpsychiatric control subjects during the eyes-open rest condition. Although relatives of bipolar disorder patients also exhibited excess gamma activity at similar electrode sites in the same condition, augmented beta activity was specific to the relatives of schizophrenia patients. Schizophrenia patients also exhibited increased anterior beta activity. Lower frequency (delta, theta, and alpha) abnormalities were evident in schizophrenia patients, while relatives of schizophrenia patients generally showed normal low-frequency composition of their resting state EEGs. In the eyes-closed condition, schizophrenia patients exhibited augmented delta activity over frontal brain regions, increased theta power over the entire scalp, and increased slow alpha activity over temporal and frontal regions. Similar EEG power abnormalities were evident in schizophrenia patients in the eyes-open condition, but increased delta activity was not focused over frontal brain regions and higher frequency alpha activity was augmented over frontal cortex. Importantly, the Val158Met polymorphism of the COMT gene was associated with low-frequency abnormalities in schizophrenia patients. Met homozygote schizophrenia patients exhibited greater delta, theta, and alpha activity than what was observed in control subjects and schizophrenia patients with COMT Val158Met genotypes containing the Val allele.
Results of the present investigation build on other studies documenting increased resting state high-frequency activity over frontal brain regions in relatives of schizophrenia patients15,17
by demonstrating that beta frequency EEG abnormalities are specific to schizophrenia patients and their relatives as compared individuals with another heritable and severe mental disorder (ie, bipolar disorder). Based on findings in children of parents with schizophrenia, Itil12
proposed that increased high-frequency beta may serve as an indicator of genetic liability for schizophrenia. In a study of siblings’ absent current psychopathology, Winterer et al17
identified augmented beta activity over frontal and temporal areas as well as posterior scalp regions in a subsample of siblings. A second study of unaffected relatives found elevated beta across the scalp in parents of schizophrenia patients and specifically in frontal and temporal scalp sites in younger relatives.15
The present investigation also revealed gamma activity to be most prominent over frontal and temporal regions, and it was these sites where relatives of schizophrenia patients exhibited augmented activity. The only other study examining gamma activity during rest failed to identify abnormalities in patients or siblings; however, the data were derived from an eyes-closed condition and reflected gamma frequencies lower than those included in the data-driven characterization of gamma in the present study.17
Thus, there is growing evidence that augmented beta activity over frontal and temporal brain regions reflects genetic liability for schizophrenia, with the present study indicating that the abnormality may be specific to schizophrenia amongst severe mental disorders and extends to higher frequencies that fall into the gamma range. Increased high-frequency activity in schizophrenia patients and their relatives have been interpreted as possibly reflecting cortical hyperexcitability. Nevertheless, cortical gamma oscillations are thought to be produced independent of external stimulation by GABAergic interneurons that are in mutual inhibition through postsynaptic potentials that oscillate around 40 Hz.47
Hence, gamma is thought to reflect inhibition of cortical neurons. A second theory posits that gamma frequency thalamic oscillations are synchronous with cortical oscillations in the presence of stimuli48
; however, given the resting state of subjects in the present study, the current findings may be reflective of inhibitory activity of interneurons while the brain is in “default mode.”49
For several decades, investigators have consistently observed increases in delta and theta activity in schizophrenia patients.8,9,13,14,18–20,24
The present study provides evidence that delta anomalies in schizophrenia are most evident over frontal brain regions in the eyes-closed resting condition. Our findings also point to augmented theta activity in schizophrenia being clearly evident across the scalp regardless of whether the eyes are closed or open during the resting state. Finally, the absence of delta and theta frequency abnormalities in bipolar disorder patients provides evidence for the augmentation of the low EEG frequencies as specific to the pathophysiology of schizophrenia. Because we found the augmentation of delta and theta activity to be only evident in the Met homozygote group of schizophrenia patients, it may be that schizophrenic pathophysiology is related to resting state functional brain abnormalities through the dopamanergic effects of the COMT Val158
Met polymorphism. The absence of an association in relatives of schizophrenia may have to do with the mechanism by which the COMT polymorphism is expressed in the development of schizophrenia. A current hypothesis about the influence of COMT on dopamanergic activity in nucleus accumbens and prefrontal cortex includes that the Met allele leads to increased tonic dopamine but reduced phasic dopamine, resulting in negative symptoms and pathophysiologic inflexibility.50
Consistent with this hypothesis, the present study revealed lifetime negative symptomatology in schizophrenia was associated with increased theta band activity. In this sample of schizophrenia patients, we have found the Met allele of the COMT Val158
Met polymorphism is also directly associated with greater lifetime negative symptomatology.51
Although alpha activity is typically less prominent when the eyes are open, it was in this condition that the schizophrenia patients showed augmented slow and fast alpha activity over frontal brain regions. Slow alpha activity was also associated with the COMT Val158
Met polymorphism with Met homozygote schizophrenia patients exhibiting an elevation in slow alpha activity compared with control subjects and schizophrenia patients of other genotypes. Despite being perhaps the most studied EEG rhythm, the neural basis for alpha activity is unknown. Therefore, it is difficult to conclude much more than that deviant corticothalamic interactions are evident in schizophrenia. Other investigations have yielded decreases in alpha activity in schizophrenia patients, rather than increases13,14,53
; however, variable findings may be attributable to whether or not frequency band powers were normalized and differences in sample characteristics such as age.13,14,16,19
There are several limitations to the present study. Nearly all patients were on psychotropic medications. Although our statistical tests indicated that EEG findings were not an artifact of medications, dependent variables could be influenced by medications, thereby diluting effects. We did find those individuals taking novel antipsychotics tended to have increased theta, alpha, and slow beta activity. Thus, this is one possible explanation for schizophrenia patients exhibiting augmented slow alpha activity over frontal regions in the eyes-open condition while relatives of schizophrenia patients showed diminished slow alpha over posterior regions. Another potential study limitation is the relatively low number of females in the schizophrenia and bipolar disorder groups. Although analyses showed that results were not due to variable gender composition across groups, a low number of women limits the generalizability of findings in the patients. Also, inclusion of some individuals with histories of alcohol or substance dependence may confound results; however, analyses indicated that history of dependence failed to be associated with EEG anomalies noted in the study. Unlike reports of beta abnormalities associated with substance dependence,54
the reported augmented beta activity does not appear to be gender specific, is only reported as significant in the eyes-open condition, and is located at frontal-temporal recording sites. Augmented beta rhythms may serve as an indicator for both the risk of alcoholism and schizophrenia, but are separable in scalp topography and the conditions in which they are observed. See Boutros et al55
for a recent review of spectral EEG characteristics as a diagnostic test for schizophrenia.
Finally, in the present study, we used PCA to derive frequency components of resting state EEGs rather than using traditionally identified frequency bands. The identified orthogonal components generally agreed with typically employed frequency cut-offs of bands, but also confirmed the need to separate alpha and beta activity into their slow and fast elements. Specifically, low-frequency EEG components consisted of delta (2–4 Hz maximum), theta (7–8 Hz maximum), slow alpha (8–9 Hz maximum), and fast alpha (10–11 Hz maximum). High-frequency EEG components were slow beta (13–15 Hz maximum), fast beta (23–25 Hz maximum), and gamma (maximal between 35 and 50 Hz). The frequency components were highly similar across eyes-closed and eyes-open conditions, suggesting that the fundamental structure of the EEG is stable across resting state conditions.
To conclude, we found evidence that high-frequency activity in resting state EEGs may function as an endophenotype for schizophrenia. Schizophrenia patients and first-degree biological relatives of schizophrenia patients exhibited increased beta activity in their resting state EEGs during an eyes-open condition. Excessive EEG high frequencies in schizophrenia may relate to anomalies of the prefrontal cortex that are neural manifestations of genetic liability for the disorder. The present study also provides evidence for augmented low frequencies in resting state EEGs of schizophrenia patients as reflective of the disorder's pathophysiology. Consistent with the presence of disorder-specific resting state functional brain abnormalities, schizophrenia patients exhibited increased activity in delta, theta, and alpha ranges, while similar anomalies were absent in bipolar disorder patients. Delta, theta, and alpha EEG frequency abnormalities were also associated with the Met allele of the COMT Val158Met polymorphism and thus supportive of the COMT gene and dopamanergic functions affecting abnormal resting brain states in schizophrenia.