El Cerebro de Homosexuales y Heterosexuales es diferente

TEP (=PET) e IRM (=MRI) muestran diferencias en asimetría cerebral y conectividad functional entre sujetos homo- y heterosexuales

PNAS July 8, 2008, vol 105, nro 27 , 9403-8

Neurociencia

TEP (=PET) e IRM (=MRI) muestran diferencias en asimetría cerebral y conectividad functional entre sujetos homo- y heterosexuales

 

Ivanka Savic* y Per Lindstrom

 

Stockholm Brain Institute, Department of Clinical Neuroscience, Karolinska Institute, 171 76 Stockholm, Sweden

 

*To whom correspondence should be addressed at: Stockholm Brain Institute, Karolinska Institute, Department of Clinical Neuroscience, Karolinska University Hospital, MR Centre. E-mail: Esta dirección de correo electrónico está siendo protegida contra los robots de spam. Necesita tener JavaScript habilitado para poder verlo..

Supporting information at www.pnas.org/cgi/content/full/ 0801566105/DCSupplemental.

 

Recientemente se encontró que las respuestas cerebrales a feromonas putativas y objetos de attracción sexual diferían entre sujetos homo y heterosexuals. Aunque esta observación puede meramente reflejar diferencias perceptivas, hace surgir la intrigante pregunta de si ciertos rasgos sexualmente dimórficos del cerebro pueden diferir entre individuos del mismo sexo pero de diferentes orientación sexual. Enfocamos este tema estudiando la asimetría hemisférica y la conectividad functional, dos parámetros que en publicaciones previas han mostrado diferencias sexuales específicas. Noventa sujetos [25 hombres heterosexuales (HomHet) y mujeres (MuHet), y 20 hombres homosexuales (HomHom) y mujeres (MuHom)]fueron investigados con volumetría de resonancia magnética de hemisferiores cerebrales y cerebelares. Cincuenta de ellos también participaron en mediciones PET de flujo de sangre cerebral, usadas para nálisis de conexiones funcionales de la amigdala izquierda y derecha. HomHet y MuHom mostraban una asimetría cerebral hacia la derecha, en tanto que los volúmenes de los hemisferios cerebrales eran simétericos en HomHom y MuHet. No se encontraron asimetrías cerebelares. Los sujetos homosexuales también mostraron conexiones de amigdala sexoatípicas. En HomHom, como en MuHet, las conexiones estaban más dispersas a partir de la amigdala izquierda; en MuHom y HomHet, por otra parte, estaban dispersas desde la amigdala derecha. Además, en HomHom y MuHet las conexiones estaban primordialmente desplegadas con la amigdala contralateral y el cingulado anterior, en HomHet y MuHom con el caudato, el putamen y la corteza prefrontal. El estudio presente muestra asimetría cerebral sexoatípica y conexiones funcionales sexoatípicas en sujetos homosexuales. Los resultados no pueden ser primordialmente adscritos a efectos aprendidos, y sugieren una vinculación con entidades neurobiológicas.

 

amygdala homosexuality cerebral lateralization cerebral connectivity magnetic resonance volumetry

 

Una de las preguntas más controversiales de la neurobiología del comportamiento humano se relaciona con los mecanismos de la orientación sexual. Este tema recibió interés creciente en la última década y fue sustanciado por resultados recientes de estudio de imagen de activación cerebral en sujetos homo y héterosexuales. Durante el juicio de atractivo de rostro y cuando se veían películas sexualmente excitantes se descubrió que la respuesta cerebral era invariante en relación con el rostro/el estímulo sexual preferido [varón en mujeres heterosexuales (MuHet) y hombres homosexuales (HomHom), y mujeres en hombres heterosexuales (HomHet) y mujeres homosexuales (MuHom)] y estaba ubicada en ciertas regiones medulares de los circuitos de recompensa y la corteza motora (1, 2). Además, en una serie de estudios PËT de activación durante el olfateo de feromonas putativas detectamos una activación del hipotálamo anterior sexualmente diferenciada en HomHet y MuHet (3) y un patrón sexoatípico (casi recíproco) de activación en HomHom y MuHom (4, 5). Si bien es intrigante, ninguno de estos estudios proveyo conclusions sobre los mecanismos subyacentes porque dieron imagines de procesos perceptivos, que podrían ser innatos tanto como aprendidos. Al indicar un vínculo entre regiones sexualmente dimórficas del cerebro medio y la orientación sexual, sin embargo, dieron combustible a la discussion en curso sobre la neurobiología de la orientación sexual e hicieron surgir varias cuestiones nuevas. Uno es si el dimorfismo sexual informado en la literatura (6) podría ser sexoatípico en sujetos homosexuales incluso respecto de factores que no están directamente asociados con el comportamiento. Otra es si las diferencias posibles entre sujetos homo y heterosexuales podrían estar presentes también en los circuitos cerebrales ajenos a los estrictamente involucraods en la reproducción.

En el studio aquí presentado enfocamos estos temas investigando grupos emparejados en edad de hombres y mujeres homo y heterosexuals en relación con dos parámetros separados, ambos sin probabilidad de ser afectados directamente por patrones y conducta aprendidas, y que dida con volumetría de resonancia magnética (RM). El segundo parámetro fue la conectividad functional de las amigdalas derecha e izquierda, analizadas basándonos en mediciones PET de flujo de snagre cerebral regional regional cerebral blood flow (rCBF) durante el descanso y el olfateo pasivo de aire no odorífero. Nuestra elección para medir los volúmenes hemisféricos estuvo basada en una encuesta de la literature actual que proveyó algunas indicaciones de lateralización sexoatípico en HomHom, y hasta cierto grado en MuHom durante ciertos tests neurosicológicos. Un ejemplo son los estudios de escucha dicótica que muestran una preferencia más pronunciada del oído derecho en HomHet comparados con HomHom (y también MuHet), en quienes no se detectó lateralización signiricativa (7, 8). Otro es el informe de que los HomHom, como las MuHet, tienen una comisura anterior relativamente más grande comparados con los HomHet (9), lo que provee un sustrato anatómico posible para conexiones interhemisféricas superiores (10). Además, los HomHom, como las MuHet, informaron superar el desempeños de los HomHet en ciertos tests verbales. Estos tests involucraban circuitos de lenguaje, que de acuerdo con algunos estudios son más simétricos en mujeres (11, 12). Las MuHom también muestra un desempeño inferior en tareas visuoespaciales, y particularmente en tests de rotación mental y estrategia de orientación (13–15). Estas funciones son procesadas primordialmente por el lóbulo parietal derecho, que as relativamente más grande en los hombres que en las mujeres (16, 17). Los datos de MuHom son escasos. Las MuHom consiguen puntajes como las MuHet en la mayoría de las mediciones cognitivas excepto en cuanto a fluidez verbal y rotación mental, dos tests en los que se desempeñan más cómo HomHet (13, 14). Se informa que tienen una preferencia levemente más fuerte en el oído izquierdo durante la escucha dicótica que las MuHet, y algunos estudios m uestran sim ilaridades con HomHet también en emisiones otoacústicas evocadas por un clic click-evoked otoacoustic emissions (CEOAEs) (13, 16, 18). Juntos, estos datos proveen una explicación racional para posibles diferencias hemisféricas globales en relación con el sexo y la orientación sexual.

La elección de medir la conectividad de la amigdala se basó en varos informes sobre lateralización diferenciada por sexo de la amigdala en el procesamiento de memorias emotivas (con una activación de la amigdala derecha en los hombres, y de la amigdala izquierda en las mujeres) (19, 20). Además, Kilpatrick et al. (21) recientemente descubrieron que la amigdala exhibe conexiones funcionales sexodiferenciadas durante el descanso: en hombres, las conexiones eran desplegadas principalmente desde la amigdala derecha y se dirigían a la corteza sensoriomotor, el striatum y el pulvinar, en tanto que en mujeres eran más pronunciadas desde la amigdala izquierda y se dirigían a la corteza subgenual y el hipotálamo. Como las mediciones de conectividad functional de estado de descanso son independientes de tareas perceptivas, cognitivas o relatives al comportamiento del usuario, se prestan a estudios de correlatos de sexo y orientación sexual neurobiológicos potenciales más crudos. Además, la amigdala as una estructura clave en las redes límbicas y exhibe alta densidad de receptores de estrógenos y andrógenos (22, 23).

 

Table 1. Volumes of interest
Group	No.	R cerebral hemisphere, cm3	L cerebral hemisphere, cm3	AI, cerebral hemispheres	R cerebellar volume,cm3	L cerebellar volume, cm3	AI, cerebellar hemispheres
HeM	25	624 ±43	612 ±41	0.012 ± 0.02*	68.2 ± 6.4	68.4 ± 6.6	-0.003 ± 0.007
HeW	25	581 ± 37	581 ±36	-0.001 ± 0.005	68.7 ± 7.4	68.4 ± 7.9	0.004 ±0.029
HoM	20	608 ±46	609 ±47	-0.0004 ±0.009	67.6 ± 6.6	67.5 ± 5.5	0.0004 ±0.025
HoW	20	548 ±34	543 ± 33	0.008 ± 0.007†	65.6 ± 7.5	65.8 ± 6.7	0.002 ± 0.020

The numbers indicate means and standard deviations. R, right; L, left; AI, asymmetry index [(R - L)/(R + L)]. *, P = 0.0005 in relation to HeW and 0.0010 in relation to HoM; †, P = 0.0244 in relation to HeW and P = 0.0344 in relation to HoM.

 

El studio presente fue desarrollado bajo la hipótesis de que:

(i) Los volúmenes hemisféricos son simétricos en MuHet pero no en HomHet;

(ii) en MuHet la amigdala está funcionalmente conectada primordialmente con la corteza subgenual y el hipotálamo, en HomHet con la corteza sonsoriomotora y el estriatum;

(iii) la diferencia lateral en volúmenes hemisféricos, así como el patron de conectividad de amigdala, pueden ser sexoatípicos en sujetos homosexuales.

 

Results

Hemispheric Volumes. HeM and HoW had significantly asymmetrical hemispheric volumes, with larger right hemisphere (P= 0.0063 for HeM and P< 0.001 for HoW; paired t tests). In contrast, no asymmetry was detected in HeW (P = 0.6054) or in HoM (P = 0.8749) [Table 1 and supporting information (SI) Fig. S1]. The ANOVA showed a significant overall group difference (P = 0.0008; F = 6.168, df = 3). Fisher’s post hoc test revealed that the asymmetry in HeM was significant in relation to HeW (P = 0.0005) and HoM (P= 0.0010). Likewise, the asymmetry index in HoW was significant in relation to HeW and HoM (P = 0.0244 and P = 0.0344, respectively). No difference was found between the HeM and HoW, or between HeW and HoM. The observed differences in asymmetry were not related to a particular hemisphere (Table 1). A post hoc evaluation detected asymmetry exceeding two standard deviations of that in HeW (who were hypothesized to have symmetrical volumes) in 1 HeW, 4 HoM, 7 HoW, and 12 HeM.

The cerebellar hemispheres were symmetrical in all four populations (P = 0.871, F = 0.236, df = 3; one-way ANOVA), without any group difference (Table 1). The inter-rater correlations was 0.85, P< 0.001, for cerebral hemispheres, and 0.93, P< 0.001, for the cerebellar hemispheres. The corresponding intra-rater correlations were 0.88 and 0.95 (P< 0.001).

Functional Connectivity. Only positive covariations are reported because only one significant negative covariation was observed [detected in HeM, with respect to the right amygdala, and located in the occipital cortex, (z = 4.5; size 5.3, Talairach coordinates 6, -80, 16)].

HeW had more widespread connections from the left amygdala, HeM from the right amygdala (Table 2). Furthermore, in HeW connections were displayed with the contralateral amygdala, the anterior cingulate and subcallosum, and the hypothalamus, whereas in HeM the connectivity clusters covered the putamen and caudate, and portions of the agranular insular cortex. Both HeW and HeM showed covariation with portions of the temporal neocortex (Tables 2 and 3 and Fig. 1).

The connectivity pattern in homosexual subjects was almost reciprocal in relation to the same-sex controls. First, in HoM the connections were more widespread from the left amygdala, in HoW from the right amygdala (Fig. 1). Second, HoM, just as HeW, displayed connections with the contralateral amygdala, the anterior cingulate, the subcallosum, and the hypothalamus. In HoW, on the other hand, connections were displayed with the putamen and the orbitofrontal and prefrontal cortex, but not with the contralateral amygdala or the cingulate cortex (Tables 2 and 3 and Fig. 1).

All four groups also showed functional connections with the temporal neocortex ipsilateral to the amygdala seed region.

 

Table 2. Significant covariations from the left amygdala

HeW HeM HoM HoW

Region

Z level

Size cm3

Coordinates

z level

Size cm3

Coordinates

z level

Size cm3

Coordinates

z level

Size cm3

Coordinates

L amygdala R amygdala Cingulate L superior and middle temporal gyrus Superior collicle

Inf 4.2 5.7 5.2 3.9

9.6 2.0 1.4 2.6 2.5

-18, 2, -18* -26, 2, -2 22, -16, -12‡ -16, 45, -4 -18, 32, -12 -14, -32, -10

inf

4.6

-18, 2, -18

inf 4.4 4.0 3.6

6.5 1.8 1.2 0.8

-18, 2, -10† 8, 6, -12‡ -30, 14, 2§ -2, 44, -12

inf     4.2     4.4

5.1     1.1     1.0

-18, 2, -10     -40, -2, -4   --34, -76, 12

Clusters detected at T = 3.0, corrected P < 0.05. Talairach coordinates denote local maxima. R, right; L, left; inf, infinite. *Includes the anterior cingulate, subcallosum, and hypothalamus, and a minor portion of the superior temporal gyrus. †Covers the hypothalamus, the subcallosum, and the anterior cingulate. ‡Covers the piriform co Table 3. rtex. §Subcallosum.

 

Group comparisons confirmed these findings: HeW, as well as HoM, showed a greater connectivity with the contralateral amygdala and the cingulate cortex compared with both HeM and HoW. In relation to HoW, HoM showed, in addition, a greater connectivity with the cerebellum, as did HeW in relation to HeM. HeM and HoW, on the other hand, showed significantly more pronounced connections with the frontal lobe cortex including the postcentral gyrus, with putamen, and the parietal cortex (inferior parietal lobe and the posterior cingulate) compared with both HeW and HoM (Tables 4 and 5 and Fig. S2). No significant differences were detected between the HeW and HoM, nor between the HeM and HoW.

Careful positioning of the amygdala volumes of interest (VOIs) on the separate reformatted PET images showed almost identical locations, and no systematic positioning shifts between the study groups.

We found no group differences in respiratory frequency (df 3, F = 1.0, P = 0.39), or amplitude (df 3, F = 2.1, P = 0.11), (Table S1).

 

Tabla 3 Significant covariations from the right amygdala

HeW HeM HoM HoW

Region

Z level

Size, cm3

Coordinates

z level

Size, cm3

Coordinates

z level

Size, cm3

Coordinates

z level

Size, cm3

Coordinates

R amygdala	inf	5.0	14, 4, -14	inf	2.4	16, 4, -14*	inf	12.0	18, 4, -14†	inf	3.4	16, 4, -14*
L amygdala + hipp +	5.0	3.4	-26, 4, -14‡				5.4	0.8	-34, 6, -8†
piri-form cortex
R orbitofrontal cortex										4.5	1.6	22, 32, -10
L putamen + insular cortex				3.6	3.0	-38, 0, -8
L middle temporal gyrus	5.0	2.6	-42,-22,-6	5.0	1.8	-42, -22, -6
L middle frontal gyrus										4.6	3.2	-26, 54, 24
										3.6	1.6	-32, 36, 40
L superior frontal gyrus										3.9	1.6	-16, 64, 16
										2.8	0.7	-12, 54, 24

Threshold at T = 3.0 and P < 0.05 uncorrected; italics indicate P < 0.1 uncorrected. Talairach coordinates denote local maxima. R, right; L, left; inf, infinite; hipp, hippocampus.

*Includes the putamen.

†Includes the anterior cingulate, subcallosum, and hypothalamus, and a minor portion of the superior temporal gyrus.

‡Covers the piriform cortex.

 

Discusion

Usando experimentos combinados TEP e IRM, encontramos dimorfismo sexual en relación con la asimetría hemisférica y las conexiones funcionales de la amigdala derecha e izquierda. También descubrimos que las ratios hemisféricas, así como los patrones de conectividad de amigdala, eran sexoatípicos en sujetos homosexuales, con HomHom exhibiendo más patrones de mujer y MuHom mostrando rasgos similares al varón (aunque menos pronunciados).

 

Methodological Issues. The investigated parameters were selected to be methodologically robust and to minimize perceptional and active cognitive interference. By carrying out MR volumetry of cerebral hemispheres, which have easily identifiable demarcations, a possible bias ascribable to cumbersome structural landmarks was minimized. The variation was further reduced by inclusion of only right-handed subjects, and by use of age-matched populations (no correction for aging effects was, thus, needed).

Left-handedness is more prevalent among HoM compared to HeM, and left-handed subjects are reported to have a less significant cerebral asymmetry than those who are strictly right-handed. A more representative population of HoM with respect to handedness would, therefore, probably show an even more pronounced symmetry. The odds for non-right-handedness are much lower in HoW (24). Consequently, the restriction to right-handed homosexual population in the present study is unlikely to explain the results.

Standard deviations were generally low and not larger in HeW and HoM than in HeM and HoW; failure to detect asymmetry can, thus, not simply be attributed to a larger variability. The present study was not designed to show how possible regional asymmetries were distributed; thus, the symmetrical hemispheric volumes in HeW and HoM could, theoretically, result from multiple regional asymmetries pointing in opposite directions. This possibility does not, however, invalidate the detected group differences.

The amygdala VOIs showed no systematic positioning shifts between the study groups. Neither were there any indications that homo-and heterosexual men and women were engaged in systematically different cognitive processes during the scans, or that they reacted differently to the experimental situation (judged by their reports, and the respiratory measurements). We, therefore, believe that the observed connectivity patterns reflected true biological differences.

Functional connectivity was in the present study calculated during rest when the subjects were lying in the scanner and breathing unscented air (without sniffing). A potential difficulty with cueing the subject to concentrate on breathing room air is that this act may constitute a task and that therefore the functional connectivity may not represent true ‘‘resting’’ condition. However, the major purpose of the present study was to investigate how the rCBF covaries between the amygdala and the rest of the brain during a condition not associated with perceptive, emotional, or cognitive tasks, which could be linked to sexual orientation or behavior. By prompting subjects to concentrate on breathing the room air we aimed to minimize variations caused by spontaneous reflections or judgments. A caveat with such approach is that individual differences in respiratory frequency and amplitude could affect the rCBF in parts of the piriform cortex and cerebellum (25, 26). Calculation of respiratory frequency and amplitude showed, however, no significant group differences (Table S1). Furthermore, respiration-related group differences in calculated functional connectivity would be primarily expected in the ventral tegmentum– pontocerebellar connections and not in the contralateral amygdala, the anterior cingulate, subcallosum, striatum, and frontal cortex. The present findings were also congruent with the major observations of Kilpatrick et al. (21), although they did not report significant connections between the two amygdalae. Bilateral amygdala connections were, however, found in females by Zald and colleagues (27), whereas Irwin et al. (28) failed to detect them in their control material, perhaps because the results were based on a mixed population of males and females.

 

Table 4. Group differences in connectivity pattern, left amygdala

Region

z level

Size, cm3

Coordinates

z level

Size, cm3

Coordinates

z level

Size, cm3

Coordinates

z level

Size, cm3

Coordinates

Group difference Anterior cingulate (subcallosum) R amygdala R parahippocampus L parahippocampus Cerebellum

3.8 3.1 3.2

HeW - HeM 2.4 -16, 32, -1 -22, 0, -18 0.3 36, -20, -24 1.4 - 23, -50, -24

6.5 3.5 4.5 3.5

HoM - HeM 4.2 -20, 2, -18 1.6 20, 32, -4 2.9 30, 10, -12* 2.0 -40, -30, -4

4.3 3.7 3.6

HeW - HoW 2.0 34, 8, -32 4.8 -16, 34,-12 2.0 3, 5,-15* 24, 2, 2

4.0 3.6 3.3

HoM - HoW 2.0 -20, 62, 12 1.3 20, -18, -12 2.8 -36, -54, -28

Group difference L amygdala Superior frontal gyrus Parietal cortex Postcentral gyrus + putamen + insular cortex

4.0 4.4

HeM- HeW 2.0 0, 22, 52 4.4 38, -66, 40 56, -26, 13‡

3.5

HeM - HoM 2.0 -18, –66, 12†

HoW – HeW No significant difference

6.2 4.2 4.1

HoW – HoM 4.1 -18, 2, -18 -4.8 -38, –64, 28 11.1 -48, -12, 1

Significances were calculated by using threshold at T = 3.0, and P = 0.05 uncorrected. HoM - HeW not significant (ns); HoW - HeM ns; HeW - HoM ns; HeM -

HoW ns. Talairach coordinates denote local maxima. R, right; L, left.

*Covers the insular and the piriform cortex.

†Posterior cingulate.

‡Includes the postcentral gyrus.

 

According to the statistical parametric mapping (SPM) method applied for functional connectivity the material was sufficient to generate inference at group level, implying that each individual was representative for his/her designated group (29, 30). The implications of the data will, therefore, be discussed at the group, and not the individual, level. With respect to MRI measurements it is noteworthy that the degree of asymmetry was in the range of those reported in previous studies, whereas the standard deviations were even smaller, although our material was relatively limited (31–33).

 

Posibles Mecanismos e Implicaciones. A pesar de diferentes abordajes metodologicos, la mayoría de lose studios sugieren que la asimetría cerebral as más pronunciada en los hombres. El grado y dirección de la asimetría, sin embargo, as espacialmente variable.

En general, la asimetr+ía es hacia la derecha en el lóbulo frontal y temporal y hacia la izquierda en las regions témporoposterior y occipitoparietal (17), y en ambas regiones más prominente en hombres (32–37). Además, en análisis de la citoarquitectura de la corteza visual primaria Amunts et al. (36) encontraron recientemente más densidad cellular cortical derecha que izquierda, lo que, otra vez, fue más prominente en hombres. Entre los estudios que comparan explícitamente los hemisferios íntegros la mayoría, aunque no todos, sugieren que el hemisferio derecho es más grandee en los hombres (32, 34, 38, 39). Los resultados presentes de la volumetría RM encajan bien con estas observaciones, así como con informes anecdóticos sobre lateralización funcional en sujetos homosexuales, hombres en particular. Una posibilidad es que reflejen más conexiones interhemisféricas más pronunciadas en MuHet y HomHom; de las mujeres se informa que tioenen una comisura anterior más grande que los hombres (40, 41), y Allen y Gorski (9) descubrieron que esta estructura era más grande en HomHom, en comparación con los HomHet. Otra posibilidad es que las funciones de los dos hemisferios no estén tan agudamente diferenciadas en MuHet y HomHom.

 

Table 5. Group differences in connectivity pattern, right amygdala

Region

z level

Size, cm3

Coordinates

z level

Size, cm3

Coordinates

z level

Size, cm3

Coordinates

z level

Size, cm3

Coordinates

Group difference Anterior cingulate (subcallosum) Hypothalamus + portion of L amygdala L amygdala Superior collicle Occippital cortex

3.8 3.3 3.8 4.0

HeW – HeM 1.6 -6,- 26, 2 1.4 --10, 2, 2 1.6 0, -27, 2 5.4 20, -70, 8

4.4 3.6

HoM - HeM 1.3 16, 4, -12 } 2.4 -10, 5, -6

4.2

HeW - HoW 1.6 -30, -6, -18

HoM - HoW No significant difference

Group difference R amygdala Precentral gyrus + putamen Orbitofr. +

HeM - HeW

HeM - HoM ns

HoW - HeW

5.3 3.5 5.3

HoW - HoM 3.2 16, 6, -14 2.4 46, 14, 36 26, 0, 12 3.3 10, 38, -8

putamen + caudate

-14, 7, 12

Frontopolar cortex Pulvinar Parietal cortex

3.4

1.1

-14, 62, 0

3.6 3.5

3.8 3.0

-18, 62, 2 8, 62, 22 -12, -54, 22

4.3 3.2 3.7

6.2 3.2 1.6 3.7

-18, 52, 34 16, 64, 16 7, -22, 16 38, -18, 20

Talairach coordinates denote local maxima. HoW - HeM not significant (ns); HeM - HoW ns; HeM - HoM ns; HoM - HeW ns; HeW - HoM ns. Orbitofr., orbitofrontal cortex.

 

HeW and HoM displayed more pronounced between-amygdala connections and greater connections with the anterior cingulate, the subcallosum, and the hypothalamus. This connectivity pattern provides a strong substrate for processing of external stimuli that are relayed by the two amygdalae and represents a possible pathway for their functional interconnection in HeW and HoM. The remarkable similarity between HeW and HoM in the connectivity pattern deserves special attention. The amygdala has a key role in emotional reactions to external stimuli, including stress; the subcallosum and the anterior cingulate, on the other hand, are highly involved in mediation of mood and anxiety-related processes (42). Affective disorders are 2–3 times more common in women than men, and the tight functional connections between the amygdala and cingulate in women is currently discussed as a possible neurobiological substrate for their higher vulnerability (43), in addition to the effects of estrogen and testosterone. Interestingly, the incidence of depression and suicide attempts is elevated in homosexual subjects, and HoM in particular (44, 45). Although the underlying mechanisms are likely to be multifactorial and include social pressure, the presently observed similarity with HeW vis-a`-vis the amygdala connectivity motivates further evaluations.

The sensorimotor cortex and striatum displayed stronger connections in HeM and HoW. These regions have been associated with attending to and acting into the external environment (the fight and flight reactions). Fight and flight reactions are reported to be more common in men (46, 47).

Los mecanismos que están detrás de las observaciones presentes son desconocidos. De acuerdo con las discusiones sobre el dimorfismo sexual del cerebro, deben tenerse en cuenta tres factores: efectos ambientales, genético e influencias de hormonas sexuales.

Se ha mostrado que la diferencia sexual en tamaño del cerebro está presente en el nacimiento (48), y algunos datos volumétricos sugieren que las diferencias sexuales en asimetría cerebral existen ya en el feto humano (49, 50), aunque otros estudios no pudieron detectarlas (51, 52). Los patrones adultos de asimetría cerebral (53), así como algunas características del dimorfismo sexual regional, son ya detectadas en niños (54). La maduración cerebral continua después de la pubertad, especialmente en los muchachos (31), lo que provee un sustrato para efectos de factores socio/ambientales. Sin embargo, atribuir tales efectos a los resultados presentes requeriría una comprensión detallada de cómo los factores ambientales específicos se relacionan con los cuatro grupos investigados, y cómo afectan los diversos circuitos cerebrales. A la luz de la información actualmente disponible esto puede ser solamente especulativo. De nota es que diversamente a estudios previos en sujetos homosexuales los datos presentes no fueron directamente dependientes de percepción o conducta. Así, aunque las estrategias específicas preferidas del sexo repetitivo (o la orientación sexual-) podrían, teóricamente, haber influido en los resultados, estos efectos sitemáticos, en lo máximo que sabemos, no han sido informados y parecen improbables.

En cuanto a los factores genéticos, la opinion actual as que pueden jugar un rol en la homosexualidad del varón, pero parecen ser insignificantes para la homosexualidad de la mujer (55). Por lo tanto, parece menos probable que los factores genéticos sean el denominador común principal para todas las diferencias grupales observadas aquí.

Los mecanismos detrás de la homosexualidad a menudo son discutidos en térmios de una subexposición a andrógenos prenatales en HomHom y sobreexposición en MuHom (56). En experimentos en animales se ha demostrado que la manipulación de testosterone altera el desarrollo de las neuronas receptoras de andrógenos al influir en las conexiones anatómnicas y patrones de muerte celular programada (57). Es interesante notar que se encontró que los monos rhesus machos tienen más receptores de andrógenos en el hemisferio derecho, en tanto que la distribución es simétrica en las hembras (58). En ratas, la asimetría cerebral del macho se establece, en parte, por la exposición temprana al andrógenos, porque la castración ene el nacimiento bloquea la asimetría nomal hacia la derecha. La simetría en hembras, por otra parte, puede ser revertida al patrópn del macho por ovariectomía neonatal (59). En qué medida estos datos son relevantes para humanos as algo que queda por clarificar.

El presente estudio no permite estrechar las explicaciones potenciales, que son probablemente multifactoriales, incluyendo el interjuego entre testosterona y estrógeno pre y posnatales, los receptores de andrógeno y estrógeno y la enzima aromatasa, que degrada la testosterona. Sin embargo contribuye a la discussion en curso sobre orientación sexual mostrando que los hombres y mujeres homosexuales diferían de los controles del mismo sexo y mostraban características del sexo opuesto en dos variables cerebrales mutuamente independientes, ue, en contraste con aquellas estudiadas previamente, no estaban relacionadas con la atracción sexual. Las observaciones no pueden ser atribuidas fácilmente a la percepción o la conducta. Si pueden relacionarse con procesos producidos durante el desarrollo fetal o posnatal es una pregunta abierta. Estas observaciones motivan investigaciones más extensas de grupos de estudio mayores y requieren una mayor comprensión de la neurobiología de la homosexualidad.

 

Methods

Subjects. Twenty-five HeM (age 30 ± 4 years), 25 HeW (age 31 ± 4 years), 20 HoM (age 32 ± 7 years), and 20 HoW (age 31 ± 5 years) were included. All subjects participated in the MR study, and 50 of them (13 HeM, 13 HeW, 12 HoM, and 12 HoW) also participated in the PET studies. All of the subjects were right-handed (60), healthy, and HIV negative. The heterosexual men and women all scored 0, the homosexual men 6, and the homosexual women on average 5.5 on the Kinsey heterosexual/homosexual scale (0 =maximally heterosexual, 6 = maximally homosexual) (61). In addition to scoring themselves on the Kinsey scale (which is based on self-identification), the subjects also participated in interviews regard­ing three dimensions of sexual orientation (fantasy, romantic attraction, and sexual behavior) over consecutive 5-year historical time periods, from age 16 to the present (5, 62). All decisions about subjects’ sexual orientation were made in ignorance of the subjects’ PET and MR data. The Ethics Committee of the Karo­linska Institutet approved the study.

 

MRI. Structural images were acquired on a GE 1.5-T scanner including 3D­weighted T1 SPGR images with 1-mm sections according to a previously described protocol (63). Homologous VOIs were delineated manually by using MRIcro software (www.sph.sc.edu/comd/rorden/mricro.html) on original, unreformat­ted T1 images by two investigators who were uninformed about the identity of the subjects, their sex, and their sexual identity. The values presented in Results and Table 1 were generated by investigator 1, who analyzed all of the data (investigator 2 analyzed data from 15 subjects in each cohort). The cerebral hemispheres were delineated on every second coronal slice of the individual MR images. The same coronal section was displayed in parallel windows, to avoid overlapping demarcation. Cerebral hemispheres were divided at the midline in the coronal plane by a hand-drawn line connecting the measured midpoint of the corpus callosum with the midpoint of the hypothalamus, third ventricle, cerebral aqueduct, and so on (38). The respective VOI included ventricles and the cortical and subcortical structures, and it ended in the caudal direction at the level of the superior colliculum (Fig. S1). Thus, the subcortical regions, brainstem, and cere­bellum were separated from the remaining brain and not included. The cerebel­lar hemispheres were delineated separately according to Ciumas and Savic (64). Fifteen pairs of randomly selected right and left cerebral and cerebellar hemi­spheres were chosen for repeated measurements by two independent investi­gators, to allow assessment of inter-rater and inter-trial reliability.

Asymmetry in hemispheric volumes (right vs. left hemisphere) was first tested in each group with paired t tests (P <0.0125). Possible group differences were then tested with respect to asymmetry indices [(right side - left side)/right side - left side/2] using one-way ANOVA and Fisher’s post hoc test (P < 0.05), separately for the cerebral and cerebellar hemispheres. The inter-and intra-rater variability was calculated by using simple regression (P < 0.05).

PET. The PET data were, in accordance with the report of Kilpatrick et al. (21), derived from multiple PET studies. These studies were carried out during percep­tion of various odorants presented in glass jars under the nose, and conducted by I.S. and colleagues at the Karolinska University Hospital (4, 5) on a scanner with a spatial resolution (FWHM) of 3.8 mm. During the baseline condition, which was the only condition used for the present analyses, subjects were instructed to relax, with eyes closed and ears plugged, and just breathe the unscented room air while an open and empty jar was presented 10 mm under the nose. Before PET scans subjects were trained to breathe normally without sniffing or hyperventilating. They were asked to restrain from active thinking during the scans, and gave verbal output in how they succeeded after each scan. rCBF was measured by using [15O]H2O during each scan, which lasted for 60 sec. The baseline scan was re­peated three times, and always separated from any sensory task scan by at least 10 min, as previously described (4, 5). For detailed description about scanning procedure, see SI Text.

Functional connectivity was defined as the extent to which normalized rCBF in seed VOIs covaried with pixel-based rCBF values across the investigated subjects. The normalized rCBF was extracted from circular (5-mm) VOIs covering the right and left amygdala (center of gravity in Talairach coordinates -18, +2, -16 and -15, +4, -14). These coordinates provided a symmetrical coverage of both amygdalae, as the standard brain is slightly rotated in Talairach space. Significant covariations (T= 3.0, corrected P < 0.05) were calculated by using the entire brain as search space (multisubject condition and covariate analysis within SPM2). Between group comparisons were carried out at T = 3.0, and P <0.05 uncor­rected, hypothesizing more pronounced symmetry in women, and thus more pronounced connections with the contralateral amygdala; furthermore, based on Kilpatrick et al. (21), we expected more pronounced connections with the anterior cingulate and subcallosum in HeW than in HeM, and more pronounced connections with the sensorimotor cortex and the basal ganglia in HeM than in HeW.

 

ACKNOWLEDGMENTS. We thank Dr. Carolina Ciumas for calculations of amyg­dala connectivity and Lovisa Kasstrom and Martin Paucar for drawing of VOIs. Financial support was provided by the Swedish Medical Research Council, the Karolinska Institute, and the Center for Gender Related Medicine at the Karo­linska Institute.

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