Functional connectivity is not based on architecture, but on the activation of neurons. Formally, functional connectivity denotes “temporal correlations between remote neurophysiological events.”90 Think of it this way: Structural connectivity maps the anatomical routes whereby neurons connect. Functional connectivity doesn’t describe what paths the connections took. It simply documents that a set of neurons were active at a given time, without supplying any information about causation.91
The Satterthwaite study took the speculations of the Ingalhalikar study and explored them directly. “Our hypothesis was that the extent to which a given subject demonstrated a stereotypically ‘male’ or ‘female’ pattern of brain connectivity would be related to the masculinity or femininity of their cognitive profile.”92 To that end, the authors created two continuous indexes. One was a score that represented the degree of masculinity or femininity in a subject’s pattern of connectivity. The other did the same thing for the subject’s pattern of scores on the Computerized Neurocognitive Battery. The authors also used a model that classified each subject as male or female on the basis of the two patterns, one for functional connectivity, the other based on the pattern on the neurocognitive tests.
In one sense, the results vindicate those who emphasize how much males and females overlap. The classification using cognitive data correctly assigned 63 percent of the subjects to their actual sex; the one using connectivity data was correct for 71 percent. That leaves 37 percent and 29 percent of the subjects for whom the classification was wrong—substantial error rates. On the other hand, the results showed as well that males and females are dimorphic in the normal sense of that term both for test scores and for neural connectivity within the brain.
The authors then demonstrated that the two indexes of masculinity/femininity were correlated. The correlation across the entire sample was +.20—statistically highly significant because of the large sample size. Two things about this result can be, and are, true at the same time. One is that the findings of the Satterthwaite study, like those of the Ingalhalikar study, represent a significant step forward. As the authors correctly note, “Our results show that sex differences in patterns of brain connectivity are related to sex-specific profiles of cognitive performance, for the first time establishing a link between sex differences in cognition and the organization of the brain’s functional connectome.”93 The other truth is that the sizes of the male-female differences are substantively modest.
A subsequent study of connectivity in the Philadelphia Neurodevelopmental Cohort (first author was Birkan Tunç) found that males had increased connectivity between the motor and sensory systems, along with increased connectivity in systems that are associated with complex reasoning and control. Males had higher connectivity in the integration of the “default mode network” that is believed to play an important role in the integration of cognitive processes. Females had increased connectivity with subcortical regions including the amygdala, hypothalamus, hippocampus, thalamus, pallidum, and others that have been associated with emotion processing, social cognition, and motivation. Taken as a whole, the results “suggest a better perception-action coordination in males, and better anticipation and subsequent processing of socially and emotionally relevant cues in females.”94
Sex Differences in the Corpus Callosum
In addition to sex differences in both structural and functional connectivity, explanations of greater interhemispheric connectivity in females naturally led neuroscientists to look at possible sex differences in the corpus callosum. The corpus callosum is a flat ribbonlike bundle of fibers about four inches long that lies at the bottom of the fissure between the two hemispheres. It is the largest white matter structure in the brain, and, as I mentioned earlier, white matter transmits information across neurons. It is the main connection that enables the left and right hemispheres to communicate. All this combines to raise the question of whether the corpus callosum differs between men and women.
In 1982, physical anthropologist Ralph Holloway and one of his students, Christine de Lacoste-Utamsing, published a small-sample study finding that the relative size of the corpus callosum was larger in females than in males and that the splenial portion (toward the back of the cerebral cortex) was more bulbous.95 For the next two decades, an assortment of technical articles appeared, some supporting and some disputing that dimorphism in the corpus callosum is real.96 As in so many other aspects of neuroscience, the advent of MRI technology and increasing sophistication in the use of that technology has enabled something resembling a consensus to emerge. In 2013, neuroscientists at the Center for Advanced Brain Imaging of the Nathan S. Kline Institute published the results for a sample of 316 normal subjects ages 18–94, using a sophisticated methodology that responded to the many issues of statistical confounding that had tripped up many earlier studies. The measure was the cross-sectional area of the corpus callosum if you sliced through the middle of it lengthwise. The technical term is the midsagittal plane. After controlling for brain size, it was found that the female corpus callosum is larger than the male corpus callosum. The estimates of the marginal means for females and males were 634 mm2 and 611 mm2 respectively, with p < .03.[97] They concluded as follows:
In this paper, it has been shown that on average, for pairs of female and male subjects with equal brain sizes and similar ages, the CCA is larger in the female by a few percent. Given that postmortem studies of callosal fibers in normal subjects have either found no difference in fiber density between sexes or a denser fiber packing in females, it can be inferred that for a given brain size, the female cerebral hemispheres are more extensively interconnected.98
Once again, the effect size is modest; once again, it is consistent with other sex differences in the brain indicating greater female symmetry in brain connectivity.
Sex Differences in Gray Matter
In 2012, a study of sex difference in gray matter provided triangulating evidence for the role of fetal testosterone in changing the male right hemisphere. Michael Lombardo was the first author of the resulting article, “Fetal Testosterone Influences Sexually Dimorphic Gray Matter in the Human Brain.” Its findings should be treated as provisional until replicated, but it gives a window into the research that is linking brain structure and function to differences in neurocognitive test scores.
The Lombardo analysis was conducted in two phases. First, neuroimaging of 28 normally developing males ages 8–11 whose prenatal testosterone had been measured through amniotic fluid established the relationship between fetal testosterone and the volume of gray matter (adjusted for differences in brain size) in brain regions of interest.99 Next, neuroimaging of 101 boys and 116 girls, also 8–11 years old, was used to assess sexual dimorphism in the same regions of interest. Boiling down a highly technical presentation, the three regions of interest showed significant sex dimorphism in both gray matter volume and in the correlations of fetal testosterone with adult gray matter volume.100
In a region of the brain in the right hemisphere that has been associated with social-cognitive and social-perceptual abilities, including empathy, greater fetal testosterone was predictive of larger gray matter volume, and the mean gray matter volume was larger for boys than for girls. The correlation of +.45 for fetal testosterone and gray matter volume fits in with collateral evidence that higher fetal testosterone correlates negatively with eye contact among infants,101 attributions of intentionality at four years of age,102 and empathy at eight years of age.103
In a region of the brain that overlaps with key language regions, including Wernicke’s area, and extends into Geschwind’s territory, greater fetal testosterone was predictive of smaller gray matter volume and girls had larger gray matter volume than boys.104 The sizable negative correlation (–.47) of fetal testosterone with the volume of gray matter is consistent with collateral evidence that higher fetal testosterone is correlated with smaller vocabulary at ages 12 and 24 months and that girls have larger vocabularies than boys at those
ages.105
In all three regions of interest, the relationships of fetal testosterone to gray matter volume were consistent with other studies involving autism, conduct disorder, and developmental language problems that disproportionately affect males.106 “In sum,” the authors concluded, “this study provides the first evidence that FT [fetal testosterone] has an organizing effect on some sexually dimorphic areas of the human brain. Along with prior work on how FT influences behavior, this work highlights FT as an important developmental mechanism contributing to sex differences in neuroanatomy.”107
There’s more on this topic that I will not try to cover (the note has some more sources for the curious), nor will I try to cover the continuing debate about the details.108 My limited point is that the debate is being conducted within a consensus among neuroscientists that the male brain is more lateralized than the female brain. The differences are consistent with observed phenotypic sex differences in visuospatial and verbal skills.
Sex Differences in Emotional Cognition and Memory
I promised that I would give you a glimpse of the progress that is being made in directly linking sex differences in the brain to sex differences in the phenotype. I chose progress in understanding sex differences in emotional response because an extensive technical literature has been accumulating and because of the intriguing links between the female phenotypic advantage in certain kinds of memory and the greater female vulnerability to depression.[109] The story that is emerging has not reached the level of settled science, but progress has been remarkable.
Emotions and some types of memory have been identified with a set of regions located deep in the temporal lobes. Five of the most important regions are the amygdala, hippocampus, thalamus, hypothalamus, and cingulate gyrus. For convenience, I will use a familiar label, “limbic system,” with the understanding that the term has fallen out of favor among neuroscientists—it amounts to “brain regions that do emotion,” with no satisfactory way of delineating what regions do and do not qualify.
The amygdala plays an important role in evaluating the emotional valence of a situation (it is famously involved in fight-or-flight decisions) and in learning through reward and punishment. It also is involved in the consolidation of emotion-laden memory.
The region most closely associated with memory is the hippocampus, located immediately behind the amygdala. Specifically, the hippocampus is key to the consolidation of long-term declarative memory—the inventory of events and facts that we can consciously call to mind. The hippocampus is especially important to episodic memory, based on events that we have observed or participated in.110
With the advent of neuroimaging, researchers soon started investigating what parts of the brain were activated when samples of men and women were exposed to emotionally loaded material. The most common stimuli were sets of pictures that evoke negative or positive responses. Negative examples are photographs of a mutilated corpse or of a prison cell. Positive examples are photographs of a child happily blowing out birthday candles or of champagne glasses clinking against a setting sun. More examples are available online.111
Male-Female Differences in Response to Sexual Stimuli
Before proceeding to other kinds of emotion, let’s get one of the obvious varieties out of the way: sex differences in response to sexual stimuli. The overall conclusion, expressed by one of the leading researchers on sex differences in emotional response, will not come as a shock: “Numerous studies have demonstrated that men are more psychologically and physiologically responsive to visual sexually arousing stimuli and display a greater motivation to seek out and interact with such stimuli.”112 Science marches on.
A biological substrate underlies that observed sex difference. It has been known for some time, through clinical studies of rodents and by studying humans who have suffered seizures near the amygdala, that both the amygdala and hypothalamus are involved in sexual behavior.113 Neuroimaging studies have now established that the amygdala and hypothalamus in humans also show significant sex differences.
The most obvious difference is that the male amygdala and hypothalamus are significantly larger than the female amygdala and hypothalamus, even after controlling for total brain size.[114] Two collateral findings indicate that size makes a difference. First, the residual size of the amygdala after neurosurgery for epilepsy has been correlated with residual sexual drive.115 Second, while many regions of the brain do not differ in size after controlling for total brain size (see Appendix 3), the ones that do differ tend to have high concentrations of sex hormone receptors.116 Brain size is most dimorphic in regions where sex hormones have had the greatest organizational effect.
The results of neuroimaging studies are consistent with the proposition that men not only react more strongly to sexual stimuli than women, but also that men and women have different neurocognitive profiles. An initial neuroimaging study in 2002 established a higher level of sexual arousal in neural activation among men, but it left open two interpretations of the results: the arousal hypothesis and the processing mode hypothesis.117 The arousal hypothesis is that men show greater brain activation because there is a simple sex difference in the magnitude of response to equivalent stimuli. The greater size of the amygdala and hypothalamus might help account for this kind of sex difference.
The processing mode hypothesis, originated by psychologist Stephan Hamann, who tested it, is that men and women use different neural pathways. If so, men and women matched on level of arousal will exhibit different brain activation patterns. That’s what Hamann found. Even after equating level of sexual arousal among the male and female participants, both through fMRI data and self-ratings, the amygdala and hypothalamus exhibited substantially more activation among males than among females.118 The activation among the females was not just less than that of men in the amygdala and hypothalamus, it was slight. As for the rest of the brain, there were no areas at all in which females showed greater activation than males.
Sex Differences in Response to Nonsexual Emotional Stimuli
The larger question is whether men and women also respond differently to emotional stimuli more broadly defined.
Emotional responses and sex differences in memory. It is a familiar conversational event for long-married couples: The wife vividly remembers a family event from many years ago that the husband has completely forgotten. Over the 1980s and 1990s, evidence accumulated that this is not a baseless stereotype. On average, women are better than men at what psychologists call “autobiographical memory.”119 It is not limited to mothers remembering events involving their children; it applies generally. Evidence also accumulated for another sex difference: Women tend to be better at remembering the minutiae of an event (labeled peripheral detail), while men tended to be better at identifying the core events (labeled gist).[120]
The advent of fMRI has enabled researchers to relate these phenotypic sex differences to sex differences in the functioning of the brain. The basic technique is to expose the subjects to pictures or films while they are undergoing fMRI. A few weeks later, the subjects are tested on their memory for the scenes they saw. With the successfully remembered scenes in hand, the investigators can then go back to the fMRI results and see which brain areas were active.
In 2003, Larry Cahill and Anda van Stegeren drew on the accumulating evidence for two relationships to make a prediction. The two bodies of evidence were, first, that the right hemisphere (which tends to play a relatively larger role in males) is biased toward the more global aspects of a scene, while the left hemisphere (which tends to play a relatively larger role in women) is biased toward finer detail; and, second, that the amygdala’s role in memory for emotional material is concentrated in its right hemisphere for men and left hemisphere for women. The prediction was that administration of a drug that impairs amygdala function for memory (propranolol) should have opposite effects on men and women, impairing memory for gist in men and memory for peripheral detail in women. The results confirmed the predictio
n.121
Repeated studies since then have elaborated on the sex differences in functioning of the amygdala. The level of neural activity in the amygdala is consistently predictive of later recall: The higher the level, the greater the probability that the scene will be remembered.122 But for both sexes, this predictiveness holds for only one hemisphere: the left amygdala in women, the right amygdala in men. An additional finding from one study provides a possible explanation of women’s better recall: When asked to rate the level of emotional arousal in the pictures they were shown, the subjects’ ratings of emotional arousal correlated with the left amygdala in both men and women. In other words, women use the same region—the left amygdala—both for emotional reactions and for encoding memory. In men, the emotional reactions occur in one hemisphere and the encoding of memory in the other. It could be part of the explanation for the greater vividness and accuracy of women’s emotional memories.
The strength and persistence of emotional responses to negative stimuli. By 2012, Jennifer Stevens and Stephan Hamann of Emory University could call upon 80 separate neuroimaging studies with a total of 1,217 participants for a meta-analysis of sex differences in brain activation in response to emotional stimuli.123
The meta-analysis indicated that both sexes used all the major elements of the limbic system along with other parts of the brain. But there were also statistically significant differences in several regions, and they formed an intriguing pattern for negative or positive emotions.
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