a quantitative dendritic analysis of wernicke's area in...

THE JOURNAL OF COMPARATIVE NEUROLOGY 327~97-111 (1993)

A Quantitative Dendritic Analysis of Wernicke's Area in Humans. 11. Gender,

Hemispheric, and Environmental Factors

BOB JACOBS, MATTHEW SCHALL, AND ARNOLD B. SCHEIBEL Brain Research Institute (B.J., A.B.S.), Division of Nuclear Medicine and Biophysics (B.J.), Office of Academic Computing (M.S.), and the Departments of Applied Linguistics (B.J.),

Anatomy (A.B.S.), and Psychiatry (A.B.S.), University of California, Los Angeles, Los Angeles, California 90024-1769

ABSTRACT This quantitative Golgi study extends our investigation of relationships between cortical

dendrite systems in humans and higher cognitive functions. Here we examine the relationship between the basilar dendrites of supragranular pyramidal cells in Wernicke's area and selected intrinsic (i.e., gender and hemisphere) and extrinsic (i.e., education and personal history) variables. Tissue was obtained from 20 neurologically normal right-handers: 10 males (M, = 52.2) and 10 females (Mage = 47.8). Several independent variables were investigated: GENDER (male, female), HEMISPHERE (left, right), and EDUCATION (less than high school, high school, and university). These were evaluated according to Total Dendritic Length, Mean Dendritic Length, and Dendritic Segment Count. A distinction was made between proximal (lst, 2nd, and 3rd order) and ontogenetically later developing distal (4th order and above) branches.

There was significant interindividual variation in dendritic measurements, which roughly reflected individuals' personal backgrounds. Females exhibited slightly greater dendritic values and variability than males across the age range examined. On the whole, the left hemisphere maintained a slight advantage over the right hemisphere for all dendritic measures when all subjects were pooled, but these differences were not in a consistent direction across individuals. Education had a consistent and substantial effect such that dendritic measures increased as educational levels increased. Dendritic differences between independent variable levels were most clearly illustrated in the total dendritic length of 3rd and 4th order branches. Distal dendritic branches appeared to exhibit greater epigenetic flexibility than proximal dendrites. The present findings concur with environmental enrichment research results in animals and suggest that dendritic systems in humans function as a sensitive indicator of an individual's (a)vocational activities. 'r) 1993 Wiley-Liss, Inc.

Key words: cerebral cortex, pyramidal cell, education, plasticity, human

In our previous report on the basilar dendrites of supragranular pyramidal cells in Wernicke's area (Jacobs and Scheibel, '931, we observed considerable interindividual variation despite relatively consistent lifespan changes in dendritic neuropil. We suggested that the personal background of the 20 individuals themselves might account for much of the dendritic variation. Mounting evidence sug- gests that the functional demands placed on a given neural structure (e.g., dendritic systems) will substantially influence the growth and "ultimate" expression of that structure (Greenough et al., '85; Black, '91). To further understanding of the relationship between personal factors and cortical histology, we quantitatively examined the same dendritic profiles vis-a-vis selected intrinsic (i.e., gender

and hemisphere) and extrinsic (i.e., education and personal history) factors.

The present study is predicated on extensive research exploring the effects of exposing non-human animals to various environmental conditions. Such animal studies have revealed a plethora of environmentally induced neural changes, including alterations in gross morphology (At- man et al., '68; Walsh et al., '71, '73; Szeligo and Leblond, '77), brain weight (Bennett et al., '69; Greenough et al., '73; Ferchmin and Eterovic, '86), cortical histology (Diamond et al., '64, '66, '72, '85; Diamond, '67; Malkasian and Dia- mond, '71; M@llgaard et al., '71; Globus et al., '73; Connor

Accepted September 4, 1992.

o 1993 WILEY-LISS, INC.

98 B. JACOBS E'I' AL.

and Diamond, '82; Turner and Greenough, '85), neurophys- iology (Leah et al., '85; Green and Greenough, '861, neuro- chemistry (Krech et al., '60, '62; Rosenzweig et al., '62, '68; Bennett et al., '64), and dendritic branching (Volkmar and Greenough, '72; Greenough and Volkmar, '73; Uylings et al., '78; Juraska et al., '80; Connor et al., '82; Bryan and Riesen, '89). These alterations appear to be responsible for the finding that enriched animals consistently outperform their nonenriched counterparts on a variety of behavioral measures (Forgays and Forgays, '52; Denenberg et al., '68; Morgan, '73; Kiyono et al., '85).

Whereas environmental diversity typically produces relatively widespread cortical alterations, the cortical consequences of formal learning tend to be more localized and are clearly revealed by dendritic branching analyses (Holloway, '66). Greenough et al. ('79) demonstrated increases in dendritic branching in adult rat occipital cortex as a result of formal maze training. Using monocular maze training in split-brain rats, Chang and Greenough ('82) documented dendritic increases in trained hemispheres over non- trained hemispheres, suggesting the dendritic consequences of training were localized to the cortical areas processing sensory information associated with the training. Similarly, Greenough et al. ('85) have shown that after rats had been trained to reach with one paw, the cortical area controlling this trained paw exhibited a more complex dendritic pattern than the area controlling the untrained paw.

Such environmental diversity studies support the long- held belief that epigenetic enrichment positively influences neural expression with beneficial intellectual ramifications (Ram6n y Cajal, 1894; Hebb, '49; Diamond, '91). Because of the difficulties associated with human hist,ological studies (Sauer et al., '83; Scheibel, '88; Simonds and Scheibel, '89; Scheibel et al., '901, research extending the environmental enrichment paradigm to humans has progressed slowly. Preliminary human investigations have begun to document possible relationships between dendritic measures and in- trinsiciextrinsic variables. Scheibel et al. ('85) recently quantified dendritic expression in the left and right inferior frontal convolutions (area opercularis-triangularis; Broca's area in the left hemisphere) and the oro-facial motor zone of the motor strip area. Although overall dendritic length did not vary significantly interhemispherically, left hemisphere (LH) pyramidal cells were composed of a larger proportion of higher order (4th, 5th, and 6th) than lower order (lst, 2nd, and 3rd) dendritic segments compared to right hemisphere (RH) cells. Broca's area also demonstrated a greater proportion of higher order basilar dendrites than the other regions. The pattern held in right-handers but was partially

TDL MDL DSC HEM1 LH RH EDUC

HS UNI PROX DIST

< HS

Ma,, SD",

Abbreviations

total dendritic length mean dendritic length dendritic segment count hemisphere left hemisphere right hemisphere education less than high school high school university proximal dendritic segments distal dendritic segments mean age standard deviation for age

reversed in left-handers. These findings were interpreted as indicating an early preponderance of dendrite growth in the non-speech-gifted hemisphere followed by enhanced LH dendrite growth coincident with its emerging functional dominance. A subsequent developmental study supported this hypothesis (Simonds and Scheibel, '89). In the posterior language region (area TA1) of a very small series, Seldon ('81a,b, '82, '85) observed LH specializations in dendritic organization and suggested the LH may be eytoar- chitecturally suited for establishing the early categorical responses necessary for phoneme identification.

Finally, Scheibel et al. ('90) demonstrated that 1) in the primary sensory strip, dendritic arbors in the area represent- ing the fingers were substantially larger and more complex than in the area corresponding to the thoracic regon, 2) both the superior prefrontal region (area 9) and the supra- marginal gyrus (area 39) were characterized by complex dendritic envelopes, and 3) these two "higher-order" association areas possessed richer dendritic arbors than the finger and thoracic sensory regions. Exceptions were three individuals whose finger area exceeded all the other areas in extent and complexity (one of these exceptions had been a typist, the other a machinist; no information was available on the third). Such correlative relationships between neural structure and function are suggestive. Dendritic trees, especially those in later developing association areas that appear to be subject to what Greenough et al. ('87) refer to as "experience-dependent synaptogenesis," may collectively reflect an individual's predominant life experiences.

The present study attempts to extend the environmental enrichment paradigm to humans. Because the focus is on Wernicke's area, one might expect an individual with a more active verbaliintellectual life to have more complex dendritic systems than an individual with less verbal/ intellectual interaction. In particular, we sought to answer the following questions: 1) Are there hemispheric asymme- tries in the length or number of supragranular basilar dendrites? 2) Are there gender differences in the length or number of supragranular basilar dendrites? 3) Does the quantity of dendritic neuropil change as a function of an individual's education level and/ or predominant lifetime experiences (e.g., occupation)? 4) If there are hemispheric, gender, or education associated changes in the quantity or distribution of dendritic systems, where on the dendritic tree are these differences manifested?

MATERIALS AND METHODS Subjects and neuronal population

The present study was based on the same subjects and neuronal populations described previously (Jacobs and Scheibel, '93). Briefly, blocks of the superior temporal gyrus immediately posterior to the posterior edge of the antero- lateral tip of the primary transverse gyrus of Heschl were removed from both hemispheres of 20 right-handed subjects (10 males between 18-78 years: M,, = 52.2; SD, = 17.4; and 10 females between 20-79 years: M, = 47.8 years; SD,,, = 20.5). Personal information on subjects (Table 1) was obtained according to guidelines approved by the UCLA Human Subject Protection Committee (no. 88-09-368) from autopsy reports, medical records, and phone interviews with the next of kin. Tissue was coded, processed by using a modified rapid Golgi technique (Schei- be1 and Scheibel, '78; Scheibel et al., '85), and serially sectioned at 120 km. Ten relatively isolated supragranular

ENVIRONMENT AND WERNICKE'S AREA 99

TABLE 1. Subject Summary--Personal Factors

Subject' Education2 Occupation/hobbies

M18 F20

F29

F31

F35 M35

F40

M43 M46 F48

F53

M56.1 M56.2 M58

M62

F69

M70

F74 M78

F79

HS UNI (English and Spanish

UNI iBA in business admin- major)

istration) HS

HS UNI (Teaching credential)

HS

HS UNI (Graduate school) HS

HS

UNI (MA in psychology1 < HS 12 years) UNI

<HS (left schoolat layears

UNI (BA in business)

<HS (2nd grade)

of age)

HS HS

UNI (BA in music)

Student Exercising, reading

Configurational management ana- lyst; sewing, reading

Motherlhomemaker; formally loan underwriter; church activities

Homemaker; cooking, sewing, crafts Sixth grade science teacher; football

coach;parkranger Retiredidisabled; formally masseuse

and laboratory technician; hiking Janitor Industrial worker Homemaker; formally executive sec-

retary; took college courses for self- improvement; reading, playing mu- sical instruments, swimming, crafts and sewing

Worked in wedding chapel; sewing; quilting

Fifth grade teacher Construction worker; disabled Music supervisor for broadcasting

Machinist; appliance serviceman;

Retired school board clerical worker;

Retired railroad worker, formally in

company

formally merchant seaman

doll clown collecting

military; church activities, TV and baseball fan

Homemaker Retired barber; formally in military,

played fiddle and harmonica Retired secretarv: Dlaved violin " . ~

'Subjects are referred to by sex (M, male; F, female) and by age in years. For example, Mi8 refers to an 18 year old male Because two male subjects were 56 years aid, they were differentiatedas M56.1 and M56.2. "HS, did not complete high school; HS, graduated from or had less than 2 years of college, UNI, graduated from or completed more than 2 years of college.

pyramidal cells per hemisphere (i.e., 20 cells per brain) were randomly chosen according to criteria described in Figure 1. All cells were traced by means of a camera lucida, entered into a computer via a digitizing tablet, and quantified with a program designed to capture the three-dimensional charac- ter of the dendritic trees.

Dependent measures The planar coordinates of dendritic branch points and

terminations (x and y values) were categorized and quantified according to the accepted somatofugal nomenclature (Bok, '59; Van der Loos, '59; Coleman and Riesen, '68; Uylings et al., '75, '86): dendritic branches arising from the perikaryon are first-order segments until they furcate into second-order segments, which branch into third-order segments, and so on (Fig. 1). A distinction was also made between proximal (lst, 2nd, and 3rd order) and distal (4th order and above) dendritic segments. This distinction was employed to detect possible differences between proximal segments, which are present and develop in the pre- and peri-natal periods, and distal segments, which are primarily a post-natal phenomenon (Ram6n y Cajal, '09, '11; Conel, '39-'67). This proximal-distal classification differs from the distinction often made between terminal and intermediate segments (Smit et al., '72; Uylings et al., '78; Juraska et al., '80; Buell and Coleman, '81). Nevertheless, the intermediate-terminal segment distinction is not completely lost because a higher proportion of terminal segments are probably found in the ontogenetically later developing distal branches.

Three measures were used to characterize the dendritic systems. The dependent variables used included three characterizations of dendritic structure. Total dendritic length (TDL) refers to the summed length of all dendritic segments. Mean dendritic length (MDL) represents the mean length of dendritic segments. Dendritic segment count (DSC) refers to the total number of all dendritic segments. These measures characterized the dendritic systems for an individual subject (i.e., 20 neurons), a given hemisphere (i.e,, 10 neurons), and/or for a particular grouping of subjects. Because the number of individuals at each independent variable level differed, values for TDL and DSC were divided by the number of subjects in each group to form adjusted values (i.e., adjusted TDL and adjusted DSC) unbiased by unequal sample sizes. This provided representative dendritic values for individual subjects and permitted subsequent comparisons of TDL and DSC across levels of independent variables.

Independent variables Four independent variables were chosen for final analysis:

sex (GENDER), education (EDUC), hemisphere (HEMI), and dendritic branch order (ORDER). Two of the independent variables (GENDER, EDUC) were between CASE (subject) factors; two (HEMI and ORDER) were within subject factors. We had initially wanted to explore possible effects of language on dendritic measures by comparing monolingual individuals with those having learned a second language. Because we could not determine language profi- ciency or use with sufficient accuracy, this variable was excluded from subsequent analyses. There were two levels for GENDER (male and female). EDUC consisted of three levels ( < HS, HS, UNI). Subjects who had not graduated from high school (HS) were placed in the less than high school (<HS) group (n = 3; all males; Ma, = 62.7, SD, = 7.0); subjects with a high school diploma but with less than 2 years of college were classified as members of the HS group (n = 9; 6 females, 3 males; Mage = 46.7, SDage = 19.5);those who had completed more than 2 years of college, or had graduated from college (including graduate school), were considered as part of the university (UNI) group (n = 8; 4 females, 4 males; Ma, = 49.0, SD, = 20.3). It was not possible to account for several factors (e.g., time since graduation, area of specialization, and school achievement). HEMI consisted of two levels (left and right) and was a within subject, repeated measures factor. The final independent variable (ORDER) differentiated between proximal (PROX) and distal (DIST) order dendritic segments.

Statistical analysis The data, 16,697 dendritic length measurements, were

analyzed on the UCLA mainframe computer (IBM 30901 6005). All analyses were run on SAS (version 6.06, '89). Inferential analyses faced severe limitations for several reasons: 1) tissue from only 20 individuals was examined; 2) each individual had a different number of dependent variable measurements, resulting in an unbalanced design; and 3) there were missing matrix cells in the analytic design (e.g., no females in the < HS group). Because of difficulties in evaluating unbalanced repeated measure designs, we attempted to aggregate the data so that each subject had a TDL and DSC measurement for ORDER and HEMI. This resulted in either 1) so few cases that the statistical power of the inferential procedure (e.g., a multivariate analysis of variance, MANOVA) was greatly compromised, or 2) so

100 B. .JACOBS ET AL.

3 f

Figure 1

ENVIRONMENT AND WERNICKE’S AREA 101

TABLE 2. Results of Multivariate Regression Analysis With Nesting

Source DF ss MS Fvalue Pr > F

many empty design cells that the procedure was unsuccess- ful. Consequently, inferential analyses could be run only on MDL values by performing an almost equivalent multivariate regression analysis with nesting. This procedure used Type I11 SS (partial sum of squares) to accommodate the unbalanced design. This design treated the CASE compo- nent as a random effect. Each MDL data point is nested within CASE, which is analogous to a repeated measures multiple analysis of variance designed to model correlated effects due to multiple measurements from the same person. The nature of this model is further characterized in the Multivariate Analysis section below. Variables were treated as between or within subject class effects in an analysis of variance. Because nesting allows one to examine the effects of a variable within the level of a factor, it was possible to examine the effect of specific predictors on the dependent variable while accounting for the differential contributions of unbalanced factors. In other words, nesting was a way of forcing the repeated measures within subject variables into the regression equivalent of a MANOVA. This provided an accurate multivariate procedure for investigating the data.

Significant nested effects in the regression would demon- strate the presence of interaction effects. Preliminary corre- lation analyses indicated some treatment of interaction effects might be necessary, but precise statistical evaluation of such effects (e.g., HEMI x GENDER x ORDER x EDUC) was not possible because of the nested nature of the design. Interaction effects were evaluated in detail graphically.

RESULTS Differences in dendritic values for independent variable

levels were most clearly shown by the adjusted TDL measure. Similar but lesser differences were revealed by MDL and adjusted DSC. This is important because only MDL measures could be analyzed inferentially. As is typical with human tissue, there was considerable interindividual variability across all dependent measures.

Multivariate analysis The multivariate nested regression analysis, which in-

cluded effects for ORDER, HEMI, and CASE, accounted for 13.5% of the variance in MDL (see Table 2). Given the considerable individual variation that typifies human tissue, it was not surprising that there was a significant CASE effect. There was a significant effect for ORDER, ORDER nested within CASE, and HEMI nested within CASE. These findings indicate that there was a significant difference in MDL between PROX and DIST dendritic branches, and that there were significant interhemispheric differences in MDL.

Interaction analyses Means and standard errors for adjusted TDL, MDL, and

adjusted DSC by levels of the independent variables are

~ ~~

44.17 0001 Model 59 6,472,074 109,696 Error 16,637 41,322,595 2,484 Corrected total 16,696 47,794,669

Source DF TypeIIISS MS Fvalue Pr > F

Order I 5,283,240 5,283,240 2,127.82 0001 Case 19 963,080 50,688 20.41 ,0001 Order (case) 19 284,648 14,981 6.03 ,0001 Hemi (easel 20 161.562 8.078 3 25 ,0001

presented graphically in Figure 2 . LH dendritic values were greater than RH dendritic values for all dependent measures. Examination of cross-gender differences showed females with greater dendritic values than males for all dependent measures. These gender differences were consistent across the seven decades represented by the sample. Overall, DIST dendritic segments were considerably longer than PROX segments (Fig. 2b) and contributed more to TDL (Fig. 2a). However, there were more PROX segments than DIST segments (Fig. 2c). As educational level increased, so did the amount of dendritic neuropil.

The results from the nested model motivated further investigation. A breakdown of MDL (means 2 SEM), adjusted TDL and adjusted DSC by independent variables is provided in Table 3, which is constructed to facilitate examination of main and interaction effects. An overview of these effects is provided by the four-way interaction (HEMI x GENDER x ORDER x EDUC) illustrated in Fig- ure 3.

There was no obvious pattern of hemispheric differences at the various combinations of GENDER, ORDER, and EDUC. ORDER results differed between measures of dendritic length and dendritic number. For adjusted DSC, PROX segment values were greater than DIST segment values across the four combinations of HEMI and GEN- DER. In contrast, dendritic length measures (MDL and adjusted TDL) revealed greater DIST than PROX length at the four HEMI x GENDER levels except for the RIGHT x MALE x HS x DIST adjusted TDL value. All three of the HS subjects (M18, M43, M78) in the RIGHT x MALE statistical cell, when compared to the other males in the study, had much lower than average values on adjusted TDL (10,047 pm vs 13,038 pm) and adjusted DSC (128 vs. 157). For all three dependent measures, both the PROX and DIST trend lines generally rose as EDUC increased regardless of GENDER or HEMI. Comparison of MALE and FEMALE trend lines showed some differences in the effects of EDUC on both dendritic length and adjusted DSC. The failure to include <HS FEMALES and the small number of subjects in each statistical cell prohibit further interpretation of the GENDER by EDUC effect.

Figure 4 shows a consistent pattern of more dendritic branches of greater length for FEMALES than for MALES.

Fig. 1. Photomicrograph and camera lucida drawing of same supragranular pyramidal neuron with soma at 850 pm from the pial surface. This cell illustrates the selection criteria: 1) the soma-apical dendrite orientation is perpendicular to the pial surface; 2) the soma is located centrally within the 120 pm section depth; 3) the apical shaft is at least 100 pm in length; 4) at least three primary basilar dendritic shafts are present, each with at least two secondary branches and their conse- quent branch systems; 5) higher order branches have natural termina-

tions; 6 ) cell exhibits no obvious evidence of incomplete impregnation; and 7) cell is relatively unobscured by adjacent neuronal structures. Each basilar dendrite (i.e,, one primary segment and all subsequent branches) was drawn in a different color to facilitate identification. No attempt was made to account for the width of the dendrites. Numbers at branching points and at dendritic terminations represent depth (z values) relative to the soma; not all z values are illustrated here. Bars, 100 pm.

102 B. JACOBS ET AL.

5 2 40000

3 :: 4 30000

8 3 G 20000 9, 3 10000

0

5 0 2 d a HEMI GENDER ORDER EDUCATION

90

80

70

X yl

b HEMI GENDER ORDER EDUCATION

C

900 , ,

LL

HEMI GENDER ORDER EDUCATION

Fig. 2. a: Adjusted Total Dendritic Length (TDL) values (rounded to nearest whole number) for all independent variables. b Mean Dendritic Length (MDL) values for all independent variables. c: Adjusted Dendritic Segment Count (DSC) values (rounded to nearest whole number) for all independent variables. Length values (in pm) and DSC values are presented in the middle of each column (note decimal point for MDL values). Error bars represent SEM. See text for details.

The GENDER difference is most clearly seen from examination of adjusted TDL.

The effect of education on dendritic neuropil is clearly illustrated in Figure 5 . A positive increasing relationship exists between EDUC level and the length and number of both PROX and DIST branches. As demonstrated by adjusted TDL, the relative contribution of DIST segments to overall dendritic length increased as education increased.

The Dendritic envelope To investigate with greater resolution which portions of

the dendritic tree were most sensitive to the effects of the independent variables, we examined the dendritic "envelope" order by order for adjusted TDL, MDL, and adjusted DSC. Adjusted TDL values peaked at the 4th order and decreased sharply thereafter. MDL values increased in dendritic values up to the 5th order. Adjusted DSC values peaked at the 3rd order, decreased slightly for the 4th order, and declined sharply thereafter. DIST segments were longer and exhibited more variation than PROX segments. The dendritic envelopes for HEMI (Fig. 6), GENDER (Fig. 7), and EDUC (Fig. 8) revealed trends for the independent variables similar to those presented above. In general, the greatest difference between levels of a given independent variable were found in 1) the 3rd and especially the 4th order segments for adjusted TDL, 2) the 4th order segments and beyond for MDL, and in 3) the 3rd, 4th, and 5th order segments for adjusted DSC.

DISCUSSION The implications of these findings are somewhat limited

by histological and methodological considerations. Many of the histological issues that characterize investigation of human brain tissue have been considered previously (Willi- ams et al., '78; Simonds and Scheibel, '89; Jacobs and Scheibel, '93). Methodological concerns specific to the present study include retrospective analyses of personal histories, individual variation in human tissue, functional localization, and sample size.

Retrospective analyses of personal histories Although correlative research on human dendritic sys-

tems requires the broadest possible social, cultural, and (a)vocational history of the individual (Scheibel et al.. 'go), legal, ethical, institutional, and compassionate concerns place severe limitations on the information that can be obtained. We collected core information on age, race, cause of death, autolysis time, and general biographical data on handedness, education, and occupation (cf. Jacobs and Scheibel, this volume) but had difficulty obtaining specific details (e.g., hobbies, language abilities, and daily activities) that could have provided additional insight into the epigenetic factors shaping the dendritic systems examined.

Individual variation in human tissue Interindividual variation has been well documented in

cortical stimulation mapping of language functions (Oje- mann and Whitaker, '78; Ojemann et al., '89; Gorden et al., '90) and in anatomical studies (Stensaas et al., '74; Wlhitaker and Selnes, '76). Such variation was also found in the present study. We incorporated factors such as gender and age to reduce unexplained interindividual variation. 1 ndivid- uals served as their own controls with regard to hemispheric differences because each hemisphere within an individual had the same history.


TABLE 3. Breakdown of MDL, Adjusted TDL, and Adjusted DSC by Independent Variables

Dependent variables Independent variables

Adjusted Adjusted WEMI GENDER ORDER EDUC CASES’ MDL-I TDL? d5c4

< HS H S

UNI

(31 55.2 i- 0.99 43,397 191 62.5 t 0 63 51,695 (81 63 9 i- 0.66 55.057

DIST PROX

1201 84.3 ? 0.67 27,328 I201 47 9 2 0.47 24,468

324 511

DIST < HS ( 3 ) 73 2 L 1 6 1 22,280 304

DIST UNI 18) 8 7 1 t 1 0 6 29,398 337 PROX < HS t3) 21,117 482 PROX HS (9 ) 48 2 L 0 72 24,526 509

DIST H S (9) 27,170 319 85 2 i 1 0 2

4 3 8 t 1 1 6

PROX UNI 16) 49 0 i 0 75 25,659 524

FEMALE MALE

(10) 63.2 i 0.59 54,177 (10) 60.8 2 0 58 49,414

857 813

FEMALE €IS (6) 63.3 f 0.75 53,843 us 1 FEMALE UNI (4) 63 1 i 0 93 54.678 866 MALE MALE MALE

< HS 13) 55 2 ? 0 99 43,397

UNI 14) 64.7 ? 0 92 55,437 HS (31 60.8 i 1.13 47,400

7117 780 857

FEMALE DIST FEMALE PROX MALE DIST MALE PROX

(10) 86.9 i- 0.95 28,952 (10, 48.1 f 0.67 25,225 (10) 81.6 ? 0.96 25,703 (10) 47.7 t 0.67 23,711

333 524 315 498

FEMALE DIST FEMALE DIST FEMALE PROX FEMALE PROX MALE DIST MALE DIST MALE DIST MALE PROX MALE PR OX MALE PROX

HS UNI

HS UNI < HS

HS UNI < HS

HS UNI

I61 (41 16) (41 ( 3 ) (31 (4) 131 13 I (4)

28.595 86.7 I 1.21 87.2 f 1.52 29,486 4 8 4 i o n 6 25,247 47.7 i 1.06 25,191 73.2 i 1.61 22,280 81.9 i 1.89 24,318 87.1 5 1.49 29,310 43.8 i 1 16 21.117 4 7 8 2 1 2 9 23,082 50 2 t 1.06 26.127

330 338 522 528 304 297 337 482

520 483

LEFT RIGHT

(201 62 1 f 0.58 26,371 (20) 62.0 t_ 0.59 25 424

425 410

LEFT LEFT LEFT RIGWT RIGHT RIGHT

< HS 131 54.7 2- 1 3 7 21,626 395

UNI (8) 62.9 t_ 0.91 27,595 439 < HS (31 55.6 i- 1.43 21,771 39 I

HS 191 63 7 t 0 89 26,866 422

HS 19) 61 z i- 0.88 24,830 406 UNI 18) 65.0 r 0.95 27.462 422

LEFT LEFT RIGHT RIGHT

DIST PROX DIST PROX

1201 84.1 2- 0.94 14,070 (20) 47.8 i 0.67 12,301 (20) 84.5 2 0.97 13,257

12,167 1201 48.0 L 0.67

167 257 157 253

LEFT LEFT LEFT LEFT LEFT L E F r RIGHT RIGHT RIGHT RIGHr RIGHT RIGHT

DIST DIST DIST PROX PROX PROX DIST DIST DIST PROX PROX PROX

< HS HS

UNl < HS

HS UNI < HS

HS UNI < HS

HS UNI

70.8 2 2 19 87.2 f 1.42 85.2 i 1.47 44.6 i 1.65 48.5 + 1.02 48.1 i 1.04 75.7 2 2.36 83.1 2 1.47 89.2 i 1.53 42.9 i_ 1 6 2

49.6 i 1 0 8 48.0 2 1.01

10,802

14,848 10,824 12,397 12,747

12,701 14,550 10,293 12,128 12,913

14,468

11,478

153 166 174 243 256 265 152 153 163 240 253 259

LEFT LEFT RIGHT RIGHT

FEMALE MALE FEMALE MALE

(10) 64.1 f 0.84 27,479 110) 60.1 ? 0.80 25,264 110) 62.3 i 0.82 26,698 110) 61.6 0 85 24,150

429 420

392 42 n

LEFT LEFT LEFT LEFT LEFT RIGHT RIGHT RIGHT RIGHT RIGHT

FEMALE FEMALE MALE MALE MALE FEMALE FEMALE MALE MALE MALE

HS UNI < HS

HS UNI

HS UNI < HS

HS U N I

64.6 i 1.08 63 3 2 1.33 54.7 2- 1.37 62.0 i 1.55 62.4 k 1 2 4 62.0 i 1.05 62.9 i 1.31 55.6 i 1.43 59.4 i- 1.64 67.2 2 1 3 7

27.356 424 27,664 437 21,626 395 25.885 418 27,526 441 26,481 428 27,014 429 21,771 391 21,515 362 27,911 416

Table 3 continued on page 104.)

104 U. JACOBS ET AL.

TABLE 3. (continued)

Dependent variables Independent variables

Adjusted Adjusted HEM1 GENDER ORDER EDUC CASES’ MDL2 TDL” DSC4

LEFT FEMALE DIST LEFT FEMALE PROX LEFT MALE DIST LEFT MALE PROX RIGHT FEMALE DIST RIGHT FEMALE PROX RIGHT MALE DIST RIGHT MALE PROX

! 10) (10) (101 (101 (10) (10) (10) (10)

87.6 I 1 3 4 14,734 12,745 48.9 2 0.!37

80.6 ? 1.30 15,407 46.7 0.92 11,85S 86 2 i 1 34 14,218 47 4 i 0 92 12,480

48.7 i 0.98 11,854 82.7 i 1 4 2 12,296

168 26 1 166 254 165 263 149 244

LEFT LEFT LEFT LEFT LEFT LEFT LEFT LEFT LEFT LEFT RIGHT RIGHT RIGHT RIGHT RIGHT RIGHT RIGHT RIGHT RIGHT RIGHT

FEhfALE FEMALE FEMA1,E FEMALE MALE MALE MALE MALE MALE MALE FEMALE FEMA1,E FEMALE FEMALE MALE MALE MA1.E MALE 1124I.E MALE

DISTAL 13s DISTAL UNI PROX €IS PROX UNI UISTAL c 11s DISTAL HS DISTAL UNI PROX < IIS PROX HS PROX UNI DISTAL HS DISTAL UNI PROX HS PROX UNI DISTAL c HS DISTAL €IS DISTAL UNI PROX i iis PROX HS PROX IJNI

88.6 i 1 7 2 86 2 i 2.14 49 3 t 1 25 4H.2 t 1.53 70.8 L 2 19 84.4 2 2.51 84.2 i 2.02 44.6 i 1.65 46 7 i 1 75 48 1 i I 42 84.8 i I 71 88.2 t 2.14 47.5 i 1.19 47.3 t 1.46 75.7 r 2.36

90.2 t 2.18 42.9 i 1.62 49.0 i 1.89 52.5 -c 1.59

78.5 i- 2 . ~ 7

14,567

12,789 12,679 14,271 14,271 14,713 10,824 11,615 12,X14 14,028 14,502 12,4;79

11,478 10,047 14,597 10,283 11,467 13.3 13

1 4 , ~

12,512

164 174 259 263 15:3 169 175 243 249 266 165 165 26!2 265 1 f,2 128 162 240 234 254

‘Values in parentheses represent the number. of individuals for each group. Ahsulute TDL and OSC values were divided by this number to ohtam adjusted values ’Mean dendritic length tMDI,i values represent the mean segment length for each group. jAdjusted total dendritic length (TDLI values represent the average summed length uf segments for each group. 4Adjusted dendritic segment count (USCI values represent the average number of xgnlents ror each group.

Functional localization Investigation of variations in the neural substrate sup-

porting behavior is difficult because 1) there is not a strict isomorphic relationship between behavior and neural substrate, especially in an association area, and 2) neurons probably support a variety of activities, both within and across individuals. Individual variability in functional localization presented a methodological concern because the same experiences may not have had the same histological effect across individuals. We could not determine whether topographically identical cortical areas in different individuals shared the same function. Because all individuals appeared to be neurologically normal, the cortical area examined was probably involved in auditory processing. To be certain that the sampled area was specifically involved in language would have required methods such as electrical stimulation mapping or positron emission tomography.

Sample size Interindividual variation is often so great in human

investigations that the data can easily be “submerged in noise” (Scheibel, ’88:355) unless there is a sufficiently large sample size. The results of the present study are all the more noteworthy because they emerged consistently from a study with 20 subjects and 400 neurons on three dependent measures. We examined more subjects and/or neurons than most human quantitative dendritic studies (e.g., Buell and Coleman, ’81; Seldon, ’82; Flood et al., ’85; Scheibel et al., ’85; Simonds and Scheibel, ’89). Although we can not generalize beyond the small number of subjects present in each statistical cell of the design, the 16,697 segments obtained from the ten cells per hemisphere of each subject suggest a certain robustness in the data. We can be reasonably certain that our results are a reliable indication of the effects of hemisphere, gender, dendritic order, and

education on dendritic structure. Given the difficulties and constraints of human histological research, the validity of conclusions can always be questioned. The present data were collected with reasonable controls and analyzed using accepted procedures. Thus, in so far as valid conclusions can be drawn from human data, the current study does contribute to our understanding of epigenetic influences on dendritic systems.

All interpretations here are limited to the neural substrate examined, namely supragranular pyramidal cells in Wernicke’s area. If other areas (e.g., the motor strip:l or other cell populations (e.g., layer IV stellate cells) had been examined, the results might have been different. The intrinsic (i.e., hemisphere and gender) and extrinsic (i.e., education, personal history) factors explored in the present study are discussed below.

Hemisphere The results of the present study do not support a strong

version of LH dendritic dominance for Wernicke’s area, but they do reinforce the complex nature of neurohistological laterality. The regression analysis revealed a significant HEM1 effect when interindividual variation was accounted for by means of nesting. Descriptively, LH dendritic v‘ ‘1 1 ues were slightly greater than RH values when all subjects were grouped, but interhemispheric differences tended to be relatively small for most individuals. Twelve of twenty subjects (six males and six females) exhibited a LH advantage in terms of TDL, only 8 of 20 (three males and five females) in terms of MDL, and 13 of 20 (seven males and six females) for DSC. This slight LH advantage is consistent with Seldon’s ( ’82) finding that the tangential extent of basilar dendrites in human auditory cortices was greater in the LH than in the RH. A much stronger LH dendritic

ENVIRONMENT AND WERNICKE’S AREA

LEFT n RIGHT

105

MA/

Q- n &I Proximal

-”

<HS HS U N I

<HS HS UNI

300 1 I

100

<HS HS UNI

cHS HS UNI

<HS HS UNI

<HS HS UNI

<HS HS UNI IHS HS UNI

<HS HS UNI

<HS HS U N I

1 I

<HS HS UNI

Education

Fig. 3. Graphic presentation of the four-way interaction between hemisphere (left, right), gender (male, female), dendritic order (proximal segments, distal segments), and education (less than high school, < HS; high school, HS; university, UNI). The three dependent dendritic measures are mean dendritic length (MDL) (top row of graphs), adjusted total dendritic length (TDL) (middle row), and adjusted dendritic segment count (DSC) (bottom row). See text for details.

advantage was also noted by Scheibel et al. (’85) for the anterior speech region (Broca’s area).

Although there are methodological differences (e.g., different subjects, sampling and quantification techniques) between Scheibel et al. (’85) and the present dendritic study, interesting ORDER differences in the two cortical areas did emerge. Wernicke’s area exhibited a greater proportion of DIST segments (TDL: 53.4%, and 52.1% for the RH

homologue) than Broca’s area (TDL: 39.7%, and 30.8% for the RH homologue), suggesting that the dendritic systems in Wernicke’s area may mature somewhat later than those in Broca’s area. This agrees with Whitaker et al. (’811, who suggest that most layers in Wernicke’s area reach their peak thickness at 4 years of age whereas a majority of layers in Broca’s area peak at 6 months. Nevertheless, laminar measures are subject to considerable individual variability

106 €3. JACOBS ET AL.

20 ' cHS HS UNI

Education

<HS HS UNI Education

6 0 0 , 1

<HS HS UNI Education

Fig. 4. Graphic presentation of the two-way interaction between dendritic order (proximal segments, distal segments) and gender (male, female). The three dependent dendritic measures are mean dendritic length (MDL) (top graph), adjusted total dendritic length (TDL) (middle graph), and adjusted dendritic segment count (DSC) (bottom graph). See text for details.

Fig. 5. Graphic presentation of the two-way interaction between dendritic order (proximal segments, distal segments) and education (less than high school, < HS; high school, HS; university, UNI J. The three dependent dendritic measures are mean dendritic length (MDL) (top graph), adjusted total dendritic length (TDL) (middle graph,), and adjusted dendritic segment count (DSC) (bottom graph). See text for details.

and heterogeneity (cf. Thatcher et al., '871, particularly for the temporal speech cortex (Rabinowicz, '86). More importantly, the results of the present investigation (as well as Seldon, '82 and Scheibel et al., '85) provide only a static view of dendritic asymmetry by ignoring possible age- related changes in dendritic laterality. A more accurate account of dendritic laterality must include a dynamic, ontogenetic perspective (Simonds and Scheibel, '89; Jacobs and Scheibel, '93).

Gender Although gender differences in dendritic systems (Dia-

mond et al., '75; Ayoub et al., '83; Juraska, '84, '86) and in cortical development patterns (Sandhu et al., '86) are well documented in animals, we are not familiar with any human research that has investigated gender differences in dendritic expression (for review, Swaab and Hofman, '84). The present results indicate that dendritic values and variation were slightly but consistently greater for females than males across the entire age range analyzed. Even in two 9 year olds (M9 and F9) subsequently examined (Jacobs and Scheibel, '93), dendritic values for all dependent measures were higher in females, suggesting that such gender differences may emerge within the first decade. It seems unlikely that the other independent variables could have collectively contributed to the observed gender differences because male and female groups were similar in age and education.

These observed gender differences provide a histological parallel to recent cerebral blood flow (CBF) and neuroimag- ing findings. Regional CBF studies have shown that females have 11-15% higher mean blood flow levels than males (Gur et al., '82; Rodriguez et al., '88). Because blood flow and glucose metabolism are normally highly coupled (Sokoloff, '81; Kennedy et al., '821, one would also expect females to exhibit higher cerebral glucose metabolic rates than males. Baxter et al. ('87) confirmed this expectation with positron emission tomography (PET) by showing that whole brain glucose metabolic rates were 19% higher and more variable in females than in males. Several explana- tions have been proposed for these gender differences (e.g., variations in brain size, influence of estrogens, and higher pulse pressure in females). As a complementary alternative, we suggest that the amount of neuropil could also partially explain such gender differences because higher resting glucose metabolic levels would be required to maintain membrane potentials across greater neuronal surface area (Chugani et al., '87). This suggestion is supported not only by the present investigation, but also by a recent magnetic resonance imaging study of 69 adults (age range, 18-80 years), where it was shown that males exhibited greater age-related atrophy than females (Gur et al., '91; cf. Takeda and Matsuzawa, '84). Whether these reported gender differences are related to the observation that aging processes tend to affect males more than females (for review, see Giaquinto, '88) along a variety of neuropsychological mea-


Fig. 6. Dendritic envelopes for the two levels of HEM1 (LEFT and RIGHT): (a) Adjusted Total Dendritic Length (TDL); (b) Mean Dendritic Length (MDL); and (c ) Adjusted Dendritic Segment Count (DSC). Dendritic branch orders 1 through 8 are represented along the abscissa. Ordinate values differ for each dependent variable. See text for details.

sures (Jarvik and Bank, ’83; Obler et al., ’85) remains unclear at present.

Education There is a long history of speculation that education and

intellectual challenge have neuroanatomical and behavioral consequences. Donaldson (1899, to cite one example, suggested nearly a century ago that education consisted of brain modifications. Recent research indeed indicates that cognitive growth in children is substantially influenced by socio-cultural-economic factors (Friedman and Cocking, ’86). It has also been suggested that education and its covariates may provide a protective brain reserve capacity that increases the threshold for detecting the clinical effects of Alzheimer’s Disease (Berkman, ’86; Stern et al., ’91). Neurologically, fewer electroencephalographic abnormali- ties have been observed in individuals from higher socio- economic backgrounds (Silverman et al., ’55). Extensive animal research on environmental diversity indicates that challenge increases the amount of dendritic neuropil. We therefore expected individuals with a richer educational background to possess more complex dendritic ensembles than individuals with less educational experience.

Education and its sequelae (see below) did appear to have a positive neurohistological effect in the present study, as exhibited by increases in all dependent dendritic measurements as educational level increased. These were among the largest and most consistent differences observed. The EDUC effect was clear even at the individual level. Seven of the eight individuals in the UNI group had TDL values greater than the overall mean, while only four out of nine in the HS group had TDL measures greater than average, and all three individuals in the < HS group were below the mean. There was also an education-related shift in the PROX/ DIST ratio. DIST segment TDL increased relative to PROX segments more for the UNI group than the other groups.

These findings require qualification. First, differences between the < HS group (n = 3; all male) and the two other levels (HS and UNI) were probably somewhat exaggerated because males tended to have lower overall dendritic values, and because the mean age of the < HS group was relatively high (M, = 62.7). These age and gender characteristics may partially explain the large discrepancy between the < HS group and other levels. The consistent differences between HS and UNI groups, however, were not saliently diminished by age or gender factors. The mean ages for both the HS (M, = 46.7) and UNI (M, = 49.0) groups were very close. There were six females and three males in the HS group, and four males and four females in the UNI group. Given that females had higher values on dependent dendritic measures than males and that there was an age-related decrease in dendritic length (Jacobs and Schei- bel, ’931, one would expect the HS group to have higher dendritic values than the UNI group, which was not the case. A second qualification concerns the term “education” itself. In the present study, education should be interpreted broadly as a form of intellectual challenge. Defined this way, the term refers to the direct influence of a formal education as well as the long term (intellectual) experiences that result from that education. Regardless of the short- term effects a university education may have on dendritic morphology, such changes would probably not maintain themselves unless there were concomitant (a)vocational activities that encouraged and supported dendritic prolifer- ation throughout a person’s life.

We cannot directly address the inevitable question of whether individuals with a university education possessed more complex dendritic systems because they had university experience, or whether they were predispositioned to attend a university because of inherently more complex dendritic systems. Although this is clearly not resolvable, environmental diversity studies on animals and most other

108 B. JACOBS ET AL.

-ll!L=u 4 5 6 7 8

Dcndntic segment order a Dendtrlic segment order

300

250

- C : 200 .= Q

oli

I/:

E

.g 150

6 a 2 loo

'!2 0

0

3 4.

50

0 1 2 3 4 5 6 7 8

Dendrtic segment ordcr C Fig. 7. Dendritic envelopes for the two levels of GENDER (FEMALE and MALE): (a) Adjusted Total

Dendritic Length (TDL); (b) Mean Dendritic Length (MDL); and (c ) Adjusted Dendritic Segment Count (DSC). Dendritic branch orders 1 through 8 are represented along the abscissa. Ordinate values differ for each dependent variable. See text for details

neurobiological research underscore the importance of the environment for shaping the cortical microenvironment beyond its major organizational features. The present study provides tentative support for extending the conclusions of three decades of animal research on the neurohistological consequences of environmental enrichment to humans. More importantly, the results provide strong evidence for the importance of intellectual challenge and related epigenetic factors by demonstrating for the first time in humans the impact education and its sequelae can have on dendritic structure.

The dendritic tree The results indicated a significant MDL difference be-

tween PROX and DIST segments. DIST branches were 76% longer than PROX branches and exhibited greater variability. Accepting that a higher proportion of terminal segments are found among DIST branches, these findings are consistent with those in humans (Buell and Coleman, '81) and animals (Smit et al., '72; Uylings et al., '78; Juraska et al., '80) documenting greater average length in terminal over intermediate dendritic segments. With regard to the number of segments, more than half are represented by the middle of the dendritic tree (3rd and 4th order segments). As in other studies (e.g., Juraska et al., '801, TDL was the best single measure differentiating levels of independent variables. Combining the greater mean length of more distal segments with the larger number of 3rd and 4th order branches, it is not surprising that 3rd and 4th order segments were particularly sensitive to differences between independent variable levels.

Proximal segments develop early ontogenetically and appear, despite possible continued growth and resorptions, to be relatively stable in the face of epigenetic influences in both animals (Carughi et al., '89) and humans (Scheibel et al., '85). Distal branches, by comparison, develop somewhat later ontogenetically and are remarkably sensitive to envi-

ronmental influences. Speculatively, these observations suggest that "higher order" environmental influences (e.g., later acquired linguistic information or formal educational endeavors) may have a preferential effect on the distal portions of dendritic ensembles.

Individual factors Not explicitly explored in the present study were the

histories of the individuals. The personal factors contribut- ing to and reflected in an individual's dendritic systems can only be surmised. Nevertheless, consistent with the finding of Scheibel et al. ('90) that an individual's occupation may affect dendritic architecture, there were two general relationships in the present data between personal characteristics and dendritic structure. Women who were more occupationally and socially active tended to have greater TDL measurements. Seven out of ten females had TDL values greater than the mean of all subjects (51,795.3 pm) (see Jacobs and Scheibel, '93). Those below the grand mean were F35, F69, and F74. F35 was an obese homemaker who suffered from a 20 year history of rheumatoid arthritis and who, 3 months antemortem, developed fatigue and dyspnea on exertion. F69 was characterized as being lethargic towards the end of her life and seemed to lead a somewhat sedentary lifestyle, with her major activities being doll clown collecting and needlepoint. F74 resided with a live-in helper, disabled because of a hip injury, and was largely bedridden. Age was not the only factor here because the oldest woman, F79, had an above average TDL value. Interestingly, she lived independently and was described as actively keeping up with recent events (e.g., politics). The woman with the highest TDL of all subjects (male or female) was F29. She appeared to have a very active life, both occupationally and socially, with many friends and opportunities for interaction. The woman with the second highest TDL value, F48, was also described as being

ENVIRONMENT AND WERNICKE’S AREA

4 5 6 Dendritic segment order a

I_ 7 8

b

i t- <HS

-8- HS

t UNI

5 6 7 Dendritic segment order

109

7

Dendritic segment order C Fig. 8. Dendritic envelopes for the three levels of EDUC (<HS, HS, and UNI): (a) Adjusted Total

Dendritic Length (TDL); (b) Mean Dendritic Length (MDL?; and (c) Adjusted Dendritic Segment Count (DSC). Dendritic branch orders 1 through 8 are represented along the abscissa. Ordinate values differ for each dependent variable. See text for details.

exceptionally active, taking college courses for self improvement.

Generally, men who had jobs requiring manual labor (e.g., janitor, machinist, and railroad worker) had TDL values below the mean of all subjects. One exception was M46 who, although he was an industrial worker, had a TDL value above the grand mean. Interestingly, he had also had two years of graduate school experience. The other exception, M18, was a high school student. Only four out of ten males had TDL values greater than the grand mean (see Jacobs and Scheibel, ‘93). The two individuals with the lowest TDL values were both males: M70, a retired railroad worker with only a 2nd grade education (lowest of any subject in the study), had been bedridden for a lengthy time before death, and M62, a tool and die maker and appliance serviceman, had been a merchant seaman, and had only 2 years of high school. Of the four males with above average TDL values, two (M35 and M56.1) were teachers. One was the aforementioned industrial worker (M46) with a graduate education, and one (M58) was a music supervisor for a movie company.

CONCLUSION In conclusion, we can address our original questions. 1)

There was a slight LH > RH difference in dendritic measures when all subjects were pooled, but these differences were not in a consistent direction across individuals. 2) Female dendritic values were slightly greater than male dendritic values across the age range examined. 3) The amount of dendritic neuropil increased with subject’s educational level and appeared to roughly reflect the individual’s predominant (a)vocational experiences. 4) Dendritic differences between independent variable levels were most clearly illustrated in the total dendritic length of 3rd and 4th order branches.

The results of the current study support what has long been documented in animals: dendritic systems proliferate in response to active interaction with novel and challenging environments. The present results also concur with other investigations on the general characteristics of dendritic systems in humans (Scheibel et al., ’85, ’90) and underscore the importance of investigating or at least controlling for the individual factors that shape dendritic neuropil (e.g., hemisphere, gender, and education) when exploring human neocortical histology. The ability of dendritic systems to provide a kind of “organic autobiography” (Scheibel, ’90: 264) underscores their remarkable sensitivity as indicators of an individual’s cognitive and behavioral interactions with the environment.

ACKNOWLEDGMENTS This study represents a portion of B.J.’s 1991 doctoral

dissertation at the University of California, Los Angeles. We thank The Journal of Corriparatiue Neurology reviewers for extremely thorough and helpful comments on previous versions of this manuscript. A preliminary report of some of these results has appeared in abstract form (Jacobs and Scheibel, ’91).

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