The authors discuss gender differences found in patients with schizophrenia. Their group is the first to explore the possibility that gender differences in schizophrenia are mediated by differences in integrative network activity, reflected in a synchronous phase of high frequency (40 Hz) gamma activity.
When considering the question "Gender: Does It Make a Difference?" the simple answer is yes-men and women do appear to experience schizophrenia differently. Over the past few decades, gender differences in the epidemiology and brain morphology of patients with schizophrenia have become increasingly more clear (for a concise analysis, see Castle et al., 2000). While these investigations have allowed researchers to learn more about the disorder of schizophrenia, studies looking at gender differences at the functional level remain lacking. Contemporary models of schizophrenia postulate that the core pathophysiology of the disorder is an abnormal temporal integration of brain networks or cognitive dysmetria (Andreasen et al., 1999). Given this assumption, our aim has been to investigate gender differences in patients with schizophrenia at the highest temporal resolution window of synchronous 40 Hz gamma event-related potential (ERP) activity.
Investigators have identified significant gender differences in the epidemiology of schizophrenia. It is now accepted that women with schizophrenia have a considerably less severe course of illness exhibited by fewer hospitalizations, shorter inpatient stays and better social adaptation compared to men (Tamminga, 1997). Research of the premorbid functioning in patients with schizophrenia has confirmed that young women perform better than young men in areas of social functioning, cognitive functioning and academic achievement (Lewine, 1981; Mueser et al., 1990). Gender differences in psychopathology have also been found, with women tending to have more mood features and fewer negative symptoms (Childers and Harding, 1990; Kulkarni, 1997). Comorbid substance abuse also appears to be gender-mediated, with more men abusing drugs and alcohol, in accordance with the general population (De Quardo et al., 1994). Finally, a difference in the age of onset between men and women with schizophrenia has also been identified, with the illness manifesting at a later age in women than in men (Castle and Murray, 1993; Faraone et al., 1994).
The other main area of gender research in schizophrenia has focused on brain morphology. Historically, most studies in this area have concentrated on the normal population. Findings have ranged from the well-documented-a substantially larger average size male brain (Lynn, 1994)-to the more detailed-females have proportionally larger Wernicke and Broca language-associated regions than males (Harasty et al., 1997). Investigators have also found a higher density of neurons in the orbital area of the female brain (Haug, 1984) and a consistently greater amount of right-left asymmetry in the planum temporale of male controls (Wada et al., 1975). The corpus callosum-the major fiber tract connecting the two hemispheres-has also been found to display sexually different dimorphism. Post-mortem studies have found that the total area of the absolute size of the corpus callosum was larger in females and that women have a more rounded and bulbous splenium of the corpus callosum (Holloway et al., 1993).
Investigations that have looked at brain structural abnormalities in patients with schizophrenia have primarily concentrated on measures of ventricular enlargement. Although there are conflicting findings, most studies have found that males with schizophrenia have a higher ventricular-brain ratio compared to females (Nopoulos et al., 1997; Flaum et al., 1990).
Of particular relevance to our hypothesis is the research into gender differences of the corpus callosum within the population with schizophrenia. While there have been numerous investigations, most have tended to look at the difference between patients with schizophrenia and controls without taking into account gender differences. One exception is a study by Nasrallah et al. (1986), which found that females with schizophrenia (relative to controls) manifested an increased thickness at the anterior and middle sections of the corpus callosum.
Exploring the Differences
Given that females with schizophrenia appear to have a consistently less severe course of illness and fewer structural brain abnormalities than males, we proposed that the gender differences were related to a higher level of interhemispheric connectivity in females. Furthermore, we felt that this optimal interhemispheric connectivity would best be elicited dynamically through an electrophysiological measure. Consequently, our group is the first to explore the possibility that sex differences in schizophrenia are mediated by differences in integrative network activity, reflected in a synchronous phase of high frequency (40 Hz) gamma activity. Recently, investigations have proposed that gamma activity may be a mechanism involved in the binding problem. This refers to the manner in which the brain is able to integrate or bind together the diverse neuronal activities relating to a single stimulus amongst the vast array of parallel processing occurring at any given time (Singer and Gray, 1995). As a mechanism for integrative processing, it could be expected that gamma activity is a useful index of interhemispheric connectivity that will further elucidate observations of gender differences in schizophrenia.
Using an auditory oddball paradigm (40 target tones and 250 background tones), we sought to specifically examine late gamma induced response to target stimuli in 40 patients with schizophrenia and 40 age- and sex-matched controls (25 males and 15 females). Narrow-band gamma activity (37 Hz to 41 Hz) was examined, as this encompasses the key frequency of 40 Hz and was also the specific frequency bin that was shown to contain the cognitively induced gamma response in our previous study (Haig et al., 2000). Data acquisition and analysis were performed in accordance with protocols previously published in Haig et al. (2000).
We found that, as a group, patients with schizophrenia had significantly reduced gamma phase synchrony, both at the anterior region (F(1,78)=4.29, p<0.042) and in the left hemisphere (F(1,78)=4.30, p<0.045). This finding is in line with numerous investigations that have indicated abnormalities in the frontal region and left hemisphere (Gruzelier, 1996). While no significant differences were found between males and females in the control group, there were significant differences between the genders in the schizophrenia group. Specifically, female patients were found to have significantly reduced global gamma phase synchrony when compared tomale patients (F(1,38)=8.80, p<0.005). Consideration of topography showedthat the global reduction was producedby significantly reduced gamma phase synchrony in the frontal region(F(1,38)=6.41, p<0.016) and left hemisphere (F(1,38)=8.57, p<0.006). The Figure displays the between- and within-group differences in late gamma phase synchrony for the left hemisphere.
Our finding of reduced gamma phase synchrony in the schizophrenia group in comparison to the controls is consistent with previous research that has reported the impaired ability to integrate spatially diffuse cerebral activities (Peled, 1999). Although a gender difference in the patient group was also found, this difference was not in the hypothesized direction. To date, there is no published literature on gender differences in synchronous 40 Hz gamma activity within the population with schizophrenia to clarify this outcome. Future studies may explore this finding by looking at gender differences in synchronous 40 Hz gamma activity in response to background stimuli (irrelevant tones) and the efficacy theory.
In summary, our investigation has demonstrated that gender differences which have been found in schizophrenia are reflected in a physiological index of information processing. The primary impact of this information for mental health care professionals is to improve prognosis through more effective treatment strategies. Consequently, we need to go further than solely examining gender differences in clinical aspects or brain structures of patients with schizophrenia. It is at the functional level that clinicians have the potential to direct point of treatment. Future investigations will need to look at how and why male and female patients differ functionally and how to modify treatment plans accordingly. Clearly, if differences were found at this level, then implications for treatment would be very far-reaching. In the future, a patient's integrative ability could be a guide to the type and intensity of treatment required. In this context, gender in schizophrenia really does matter.
Andreasen NC, Nopoulos P, O'Leary DS et al. (1999), Defining the phenotype of schizophrenia: cognitive dysmetria and its neural mechanisms. Biol Psychiatry 46(7):908-920 [see comment].
Castle DJ, Murray RM (1993), The epidemiology of late-onset schizophrenia. Schizophr Bull 19(4):691-700.
Castle DJ, McGrath J, Kulkarni J, eds. (2000), Women and Schizophrenia. Cambridge, England: Cambridge University Press.
Childers SE, Harding CM (1990), Gender, premorbid social functioning, and long-term outcome in DSM-III schizophrenia. Schizophr Bull 16(2):309-318.
De Quardo JR, Carpenter CF, Tandon R (1994), Patterns of substance abuse in schizophrenia: nature and significance. J Psychiatr Res 28(3):267-275.
Faraone SV, Chen WJ, Goldstein JM, Tsuang MT (1994), Gender differences in age at onset of schizophrenia. Br J Psychiatry 164(5):625-629.
Flaum M, Arndt S, Andreasen NC (1990), The role of gender in studies of ventricle enlargement in schizophrenia: a predominantly male effect. Am J Psychiatry 147(10):1327-1332 [see comment].
Gruzelier J (1996), Lateralised dysfunction is necessary but not sufficient to account for neuropsychological deficits in schizophrenia. In: Schizophrenia: A Neuropsychological Perspective, Pantelis C, Nelson HE, Barnes TRE eds. Chichester, England: John Wiley & Sons Ltd.
Haig AR, Gordon E, Wright JJ et al. (2000), Synchronous cortical gamma-band activity in task-relevant cognition. Neuroreport 11(4):669-675.
Harasty J, Double KL, Halliday GM et al. (1997), Language-associated cortical regions are proportionally larger in the female brain. Arch Neurol 54(2):171-176.
Haug H (1984), Macroscopic and microscopic morphometry of the human brain and cortex. A survey in the light of new results. Brain Pathol 1:123-149.
Holloway RL, Anderson PJ, Defendini R, Harper C (1993), Sexual dimorphism of the human corpus callosum from three independent samples: relative size of the corpus callosum. Am J Phys Anthropol 92(4):481-498.
Kulkarni J (1997), Women and schizophrenia: a review. Aust N Z J Psychiatry 31(1):46-56.
Lewine RR (1981), Sex differences in schizophrenia: timing or subtypes? Psychol Bull 90(3):432-434.
Lynn R (1994), Sex differences in intelligence and brain size. Personality and Individual Differences 17:257-271.
Mueser KT, Bellack AS, Morrison RL, Wixted JT (1990), Social competence in schizophrenia: premorbid adjustment, social skill, and domains of functioning. J Psychiatr Res 24(1):51-63.
Nasrallah HA, Andreasen NC, Coffman JA et al. (1986), A controlled magnetic resonance imaging study of corpus callosum thickness in schizophrenia. Biol Psychiatry 21(3):274-282.
Nopoulos P, Flaum M, Andreasen NC (1997), Sex differences in brain morphology in schizophrenia. Am J Psychiatry 154(12):1648-1654 [see comment].
Peled A (1999), Multiple constraint organization in the brain: a theory for schizophrenia. Brain Res Bull 49(4):245-250.
Singer W, Gray CM (1995), Visual feature integration and the temporal correlation hypothesis. Annu Rev Neurosci 18:555-586.
Tamminga CA (1997), Gender and schizophrenia. J Clin Psychiatry 58(suppl 15):33-37.
Wada JA, Clarke R, Hamm A (1975), Cerebral hemispheric asymmetry in humans. Cortical speech zones in 100 adults and 100 infant brains. Arch Neurol 32(4):239-246.