A Comparative Neuroanatomical Study on the Metabolic Components in Executive Versus Motor Regions of the Basal Ganglia

A COMPARATIVE NEUROANATOMICAL STUDY ON THE METABOLIC COMPONENTS IN EXECUTIVE VERSUS MOTOR REGIONS OF THE BASAL GANGLIA

A thesis submitted to the Kent State University Honors College in partial fulfillment of the requirements for University Honors

LaKaléa J. Wilson

May, 2015 Thesis written by

LaKaléa J. Wilson

Approved by

______, Advisor

______, Chair, Department of Anthropology

Accepted by

______, Dean, Honors College

TABLE OF CONTENTS

LIST OF FIGURES…..…………………………………………………………………..iv

LIST OF TABLES………..………………………………………………………………v

ACKNOWLEDGMENT………………..………………………………………………..vi

CHAPTER

I. INTRODUCTION………………………………....…………….………1

Comparative Studies……………………………………………………..1

Using Primates for Comparative Studies………………………………...2

Brain Evolution…………………………………………………………..4

Metabolism: The Glia to Neuron Ratio…………………………………..8

II. METHODS…………...…………………………………………….……11

Specimens………………………………………………………………..11

Sample Processing……………………………………………………….12

Statistical Analyses………………………………………………………14

III. RESULTS………………………………………………………………..15

IV. DISCUSSION & CONCLUSION..………………………………………19

WORKS CITED…..……………………………………………………………….….....23

iii

LIST OF FIGURES

Figure

1. Primate Phylogeny of Species Investigated in this study…………………………4

2. The Executive and Motor Loop of the Basal Ganglia…………………………….8

3. Basic Anatomy of the Basal Ganglia……………………………………………...9

4. The Striatum: Caudate and Putamen……………………………………………..13

5. The Globus Pallidus Internus…………………………………………………….13

6. Image of Glia and Neuron Cells…………………………………………………15

7. Glia to Neuron Ratio: Striatum…………………………………………………..18

8. Glia to Neuron Ratio: Globus Pallidus Internus…………………………………18

9. Glia to Neuron Ratios Compared to Brain Size……………………………...19-20

a. Caudate………………………………………………………………………19

b. Putamen………………………………………………………………………19

c. Anteromedial Globus Pallidus Internus……………………………………...20

d. Intermediate Globus Pallidus Internus……………………………………….20

LIST OF TABLES

Table

1. Glia to Neuron Ratio for each Species and Sampling Region…………………...16

ACKNOWLEDGMENTS

The person that I want to thank the most is my thesis advisor and faculty mentor Dr.

Mary Ann Raghanti. I appreciate your guidance, support, and understanding throughout this entire experience. It was truly an honor to work in your lab and to be a part of your research team. Completing an honors thesis is one of my biggest accomplishments at Kent State

University, and I would not have been able to complete this task had it not been for you.

I would also like to thank my thesis defense committee Dr. Linda Spurlock, Dr. R.

Treichler, and Dr. Sara Newman. Dr. Spurlock you were the first person to commit to being a part of my defense committee when I decided to complete an honors thesis, you laughed at all my jokes during my oral defense, and you have always given me solid advice. Dr. R.

Treichler I appreciate you agreeing to be a part of my thesis defense committee. You asked the tough questions, challenged me to think deeper, and set high expectations for the defense.

Dr. Sara Newman you were the final addition to my defense committee. I am so grateful that you agreed to be a part of my thesis defense committee, you added a different perspective to the conversation.

I would like to thank the McNair Scholars Program for giving me the opportunity to complete research over the past four years and introducing me to Dr. Raghanti. I would like to thank Ms. Victoria Bocchichio, who has been helpful and supportive throughout the entire process.

This research was supported by the National Science Foundation (NSF BCS-0921079 and NSF BCS-1316829).

CHAPTER 1

INTRODUCTION

Comparative Studies

The human brain is amazingly complex, and despite more than a century of research, we know very little about what sets it apart from the brains of other species. We know that the human brain is larger than expected for an anthropoid of our body size

(Holloway, 1979), but this alone cannot account for human-specific cognitive and behavioral attributes. The goal of the present research was to determine if metabolic components of the basal ganglia circuits were altered in the evolution of the human brain, potentially contributing to differences in cognitive and behavioral capacities.

Comparative studies attempt to answer questions of human specializations and often include diverse primate species. Comparative neuroanatomy focuses on the differences among species in terms of size, structure, and microanatomy. These studies are vital to understanding the relationships among structure, function, and behavior. In other words, comparative neuroanatomical studies look at how the brain varies in terms of its cellular makeup, cytoarchitecture, fiber systems, nuclei, axons and dendrites, and the supporting matrix of glia cells, neurotransmitters, and neuroreceptors (Holloway et al., 2009). The differences discovered can then be interpreted in terms of variability in behaviors and cognitive abilities (Holloway et al., 2009).

Many characteristics of the brain are conserved across species. For example, all species have neuron and glia cells. However, glial cells within the macaque, the baboon, and the chimpanzee may co-localize with different chemicals, and these differences in some cases may be species-specific (Sherwood et. al 2012). It is important to note that it is not necessarily the structure of the brain that is variable, but also the input and output of cells that determine the actual function of the brain as well. Comparative studies try to determine how unique a species actually is, how that species became so specialized, and what factors selected for those specializations (Gazzaniga 2007).

Humans and other primates share similarities socially, genetically, and behaviorally. However, humans have developed bipedalism, a non-honing canine complex, material culture, tool use, organized hunting, language, and dependence on domesticated foods (Larsen 2010). Differences between non-human primates and humans exist because primates and humans have been on different evolutionary tracks and have had different natural selection pressures for at least six to seven million years (Larsen

2010).

Using Primates for Comparative Studies

In order to conduct a comparative study, it is important to consider which species to include. In terms of comparative neuroscience studies, it is imperative to look at a multitude of species to accurately determine the similarities and differences across genera. Sherwood and colleagues (2012) noted that there was a severe lack of 3

comparative data for the same neuroanatomical variables across a broad range of species, hampering our ability to interpret species’ differences.

Comparative studies have shown that humans and nonhuman primates are quite similar. Initial comparisons showed that chimpanzees share ninety-nine percent of our

DNA, gorillas share ninety-eight percent of our DNA, while orangutans share ninety- seven percent of our DNA (Chimpanzee Sequencing and Analysis Consortium; Scally et al., 2012;Locke et al., 2011). Despite the genetic similarities, significant differences exist.

For example, there is a mutation that is associated with dementia in humans, but the same mutation appears to have no adverse effect in gorillas. Further, great apes appear to be resistant to several diseases that affect humans (e.g., AIDS, hepatitis, and Alzheimer’s disease) (Barreiro et al., 2010). It is necessary to compare humans with a diverse range of primates in order to determine human-specific characteristics. Within the primate phylogeny, the great apes are closely related to humans, with chimpanzees being the closest living relative (Figure 1). Analyses of chimpanzees, gorillas, and orangutans, as well as other primates, will greatly enhance our understanding of how cognitive function has evolved within humans. Furthermore, comparative studies of primate neurobiology are the only source of evidence we have with respect to human brain evolution beyond what we can directly infer about brain size and cortical surface features from the fossil record (Holloway, 1968; 2000)

Figure 1: Primate phylogeny including the species investigated in this study.

Past comparative studies have revealed that areas within the human brain are much larger than in any other primate brain. For example, area 10 in the prefrontal cortex is twice as large in humans relative to other hominoids (Semendeferi et. al, 2001).

Another interesting aspect of Semendeferi’s research was that humans and chimpanzees showed similarities in area 10 of the prefrontal cortex, as well as the surrounding areas adjacent to areas 10. The frontal pole cortex of chimpanzees resembled the human frontal pole in terms of column width, neighboring cells, and cell border.

Interestingly, comparative studies further revealed that body weight explains 62% to 92% of the variation in brain size across primate species (Stephan et. al, 1988). This 5

means that primates that have larger body sizes are expected to have larger brain sizes as well (Rilling, 2006). The larger brain size (both absolute and relative) within some primates may contribute to cognitive differences across species.

Brain Evolution

In the hominid (humans and their bipedal ancestors) line, the relative brain size increased dramatically (Roth 2002). Human brains have expanded from 350 cc three to four million years ago, to their present size of approximately 1500 cc (Falk et al., 2000).

The human brain is four to five times larger than would be expected for an average mammal of its size (Jerrison, 1991), and three times larger than expected for an anthropoid of the same body size (Falk, 1980). It is important to note that brain size cannot alone explain the uniqueness of human cognition and behavior. There are other mammals (e.g., whales and elephants) that have larger brains. A whale’s brain is approximately five times larger than that of a human (Striedter, 2005). Another aspect of the brain that neuroscientists look at is how encephalized an animal is, which can be determined by relative brain size. Relative brain size is determined by using a ratio of brain size relative to body weight. While the whale may have an absolutely larger brain than a human, the whale’s brain makes up 0.01% of its body weight whereas a human’s brain makes up 2% of its body weight. Paleoneurologists also agree that brain size relative to body size (“relative cranial capacity”) is perhaps more meaningful than brain size alone, indicating that humans have a large brain relative to other primate species of the same size (Falk, 1980).

However, the human brain has not only increased in size but has likely also been subjected to reorganization. Fossil evidence shows that reorganization likely preceded large-scale brain increases in the human lineage (Holloway et. al, 2009, Holloway 1975; see also Galaburds & Paedya 1982). Holloway suggested that evolutionary changes in cognitive capacity are the result of brain reorganization, rather than changes in size alone

(Holloway Jr., R.L., 1966).

The region of the brain that has developed most in human evolution is the cerebral cortex. The cerebral cortex is involved in sensory perception, generation of motor commands, spatial reasoning, conscious thought, and in humans, language (Kandel et. al,

2000). Neurologists have studied the expansion of the cerebral cortex, and its role in mediating higher cognitive functions. The prefrontal cortex is involved in executive functions such as planning, working memory, attention, problem solving, verbal reasoning, inhibition, mental flexibility, multi-tasking, and initiation and monitoring of actions (Chan et. al, 2008). Executive functions can best be described as “the highest order of cognitive ability” (D’Espito & Grossman 1996).

While the cerebral cortex has been implicated in executive functions, the prefrontal cortex does not act in isolation. Rather, it is a part of a circuit that relies on subcortical structures such as the basal ganglia. The basal ganglia consist of the striatum, the globus pallidus, and the subthalamic nucleus (Maurice et. al, 1999). The striatum

(caudate nucleus and putamen) is the target of cortical input to the basal ganglia, and the globus pallidus is the source of the output to the thalamus and is divided into an internal and external segment (Maurice et. al 1999). 7

The basal ganglia are divided into separate closed-loop systems, including the executive loop and the motor loop (Figures 2 & 3). In the executive loop, information from the prefrontal cortex (areas 9 and 46) is received by the caudate nucleus. Then the caudate nucleus sends the information to the anteromedial Gpi, and the information goes from the anteromedial GPi to the thalamus and sent back to the prefrontal cortex (Kandel et. al,

2000).

The motor loop involves somatosensory cortical areas which send information to the putamen. The dorsolateral putamen receives information from the leg and foot region.

The putamen then sends the information to the intermediate GPi, and the information is received by the thalamus which sends the information back to the premotor cortex

(Haber, 2003). Virtually all information that is processed through the cortex must also go through the basal ganglia and, as the cerebral cortex expanded in primate and human evolution, the basal ganglia were forced to adapt to integrate more information.

Figure 2: The Executive Loop (left) and the Motor Loop (right) of the basal ganglia. (Adapted from Grahn et al. 2009; Seger 2006)

Figure 3: The basic anatomy of the basal ganglia. This diagram shows the direction of connections (gold arrows) and represent dopaminergic modulation of the basal ganglia (pink arrows).

Metabolism: The glia to neuron ratio

An indirect measure of metabolic support supplied to neurons can be obtained by examining the ratio of glia to neurons (Grossman et. al, 2004). The local density of glia in the normal brain provides an indication of the metabolic demand of neighboring neurons.

Indeed, because adult neocortical neuron numbers are attained at around the time of birth in humans, the tremendous growth of the neocortex during postnatal development is due to elaboration of dendritic arbors and a 4-fold increase in glia cell numbers (Koenderink et. al, 1994; Larsen et. al, 2006). These results suggest that more glia were produced in

the larger brains so that they could provide metabolic support to neurons that are increasingly energetically expensive in a larger neocortex such as in humans (Sherwood et. al, 2006).

The human frontal cortex displays a higher ratio of glia to neurons than in other anthropoid primates, but this difference scales with brain size (Sherwood et. al, 2006).

According to the studies conducted by Herculano-Houzel (2011), glucose use per neuron is remarkably constant, varying only by 40% across six species of rodents and primates

(including humans). The increased glia to neuron ratio in the human frontal cortex might be explained by energy expenditures that are correlated with increasing neocortex size, which accounts for 44% of the human brain’s total energy consumption (Lennie, 2003).

Evidence from comparative studies of gene expression and evolution suggest that human neocortical neurons may be characterized by unusually high levels of energy metabolism. Although the human brain comprises only 2% of body mass, it captures 20% of the body’s total glucose utilization (Sokoloff, 1960). Expansion of the human brain entailed high metabolic costs (Aiello et. al, 1995). Since mammals and other primates have smaller brains, their metabolic energy costs are much lower than that of humans due to their lack of an enlarged frontal cortex.

The goal of the present research was to determine if metabolic components of basal ganglia circuits were altered in the evolution of the human brain, potentially contributing to differences in cognitive and behavioral capacities. Specifically, our research question was to see if humans deviated significantly from other primate species in the input and output structures of the basal ganglia to support human specific cognitive 11

functions. We compared metabolism by quantifying the glia to neuron ratio in regions associated with executive functions (caudate nucleus and anteromedial GPi) versus motor functions (putamen and intermediate GPi) across a variety of primates, including humans.

The hypothesis was that humans will have preferentially increased the glia to neuron ratio in the executive loop structures (caudate nucleus and anteromedial GPi) relative to the motor structures (putamen and intermediate GPi) to support human-specific cognitive skills.

CHAPTER 2

METHODS

Specimens

Brain samples from thirty-five individuals representing six different anthropoid species were used for quantitative analyses within the striatum (caudate nucleus and putamen). The subjects included the New World capuchin monkey (n=5), two Old World monkeys: pigtailed macaque (n=6) and the baboon (n=7), two great apes: the gorilla

(n=6) and the chimpanzee (n=5), and humans (n=6). For the globus pallidus, brains from twenty-nine individuals representing six different anthropoid species were used. The subjects included the New World capuchin monkey (n=5), two Old World monkeys: pigtailed macaque (n=4) and the baboon (n=6), two great apes: the gorilla (n=4) and the chimpanzee (n=4), and humans (n=6). All individuals were adult and none of the subjects died of neurological diseases. Only the left hemisphere was used for these analyses.

Although the capuchin is not as closely related to humans and are further away in terms of lineage compared to the other primates, capuchins were included in this study as they are highly encephalized and quite intelligent, being the only New World species that routinely uses tools in the wild (Phillips et. al, 2008)

12 13

Sample processing

Caudate

Putamen

Figure 4: Nissl-stained section of a Figure 5: Two nissl-stained sections with the capuchin with the sampling regions sampling regions indicated (anteromedial GPi and within the caudate and putamen intermediate GPi). indicated.

Within the striatum (i.e., the input structures of the basal ganglia), we sampled

areas within the caudate nucleus and the putamen (Figure 4). The area of the caudate

nucleus that we examined receives information from the prefrontal cortex (Brodmann’s

Areas 9 & 46) and is involved in working memory, the perception & inference of mental

states, strategic planning processes, theory of mind and emotion recognition, and mental

flexibility (Frith et al., 2006; Levy et al., 2000; Barbas, 2000; Kempt et al., 2012). In the

putamen, we examined a region that is involved in somatomotor functions controlling the

leg & foot (Künzle 1975). No differences were expected within this motor region among

primate species.

For the globus pallidus (i.e., the output structures), we sampled within the

anteromedial GPi and the intermediate GPi (Figure 5). The area of the anteromedial GPi

that we examined receives information from the prefrontal cortex (Brodmann’s Areas 9

& 46) and the caudate nucleus and is involved in working memory, the perception and 14

inference of mental states, strategic planning processes, theory of mind and emotion recognition, and mental flexibility (Frith et. al, 2006; Levy et. al, 2000; Barbas, 2000;

Kemp et. al, 2012). The area of the intermediate GPi that we examined is involved in somatomotor functions, and communicates with the putamen and the motor cortex. No differences were expected within this motor region among primate species.

Brain samples were cryoprotected in a series of sucrose solutions (10%, 20%, and

30%) until saturated. Samples were then frozen on dry ice and cut at 40 μm using a freezing sliding microtome (Leica SM2000R). Every tenth section was Nissl-stained in order to reveal cell somata. The Nissl-staining procedure included dehydrating the sections in chloroform and graded solutions of ethanol. Then the slides were rehydrated, stained with 0.05% cresl violet, dehydrated once again, and then cleared with citri-solv and coverslipped with DPX. The Nissl-stained sections were then used to define regional boundaries and for neuron and glia cell densities.

There were approximately four sections per individual spanning the areas of interest that were used for stereological quantification of neurons and glia cells. Neuron and glia cell densities were acquired using the optical disector probe (StereoInvestigator software, MBF Bioscience). Contours were drawn around the regions of interest using a low objective (4x). Neuron and glia cells were counted at high magnification (60x).

Neurons were identified based on the presence of a centrally located nucleolus, a distinctive nucleus, visible cytoplasm, presence of dendritic processes, and larger cell body size. Glial cells were identified by heterochromatin clumps, sparse cytoplasm, and smaller cell body size (Christensen et. al, 2006) (Figure 6). 15

Figure 6. High magnification (100x, 1.4 NA) photomicrograph of a neuron and glia cells. Statistical Analyses

The glia to neuron ratio was analyzed among primate species using a mixed- model ANOVA (analysis of variance) for each the striatum and globus pallidus internus.

In the striatum, area (caudate nucleus and putamen) was used as the within-subjects variable and species as the between-subjects variable. In the globus pallidus internus, area

(GPi anteromedial and GPi intermediate) was used as the within-subjects variable and species as the between-subjects variable. For further analysis, a LSD (least significant difference) post hoc test was used to evaluate significant difference between species in the striatum and globus pallidus internus. Linear regression was also used to determine if human glia to neuron ratios differed significantly from allometric expectations based on brain size.

CHAPTER 3

RESULTS

The average neuron and glia densities for each species and area are listed in Table

1. The ANOVA for the striatum showed that the main effect of area was not significant

(F1,29 = 2.09, p = 0.16), neither was the interaction of area *species (F5,29 = 2.15, p =

0.09). However, there was a significant effect of species (F5,29 = 11.10, p < 0.01; Figure

8). Least Significant Differences (LSD) post hoc tests of the significant main effect of species revealed that humans possessed higher glia to neuron ratios than all species except chimpanzees (all p’s < 0.05). Chimpanzees also had higher glia to neuron ratios than all species except humans (all p’s < 0.05). Similarly, the ANOVA for the globus pallidus revealed a significant main effect of species (F5,23 = 4.67, p < 0.01; Figure 9).

The main effect of area was not significant (F1,23 = 0.49, p = 0.49), neither was the interaction (F5,23 = 1.56, p = 0.21). LSD post hoc tests revealed that humans had higher glia to neuron ratios than all species (all p’s < 0.05). No differences detected among the nonhuman primates.

The linear regression of glia to neuron ratios relative to brain size for each area revealed that glia to neuron ratios scaled with increases in brain size in the caudate nucleus (y = -12.71 + 2.86x, F = 17.91, p = 0.01, R2 = 0.82; Figure 10a) and putamen (y

= -16.14 + 3.57x, F = 11.29, p = 0.03, R2 = 0.74; Figure 10b), but not in the anteromedial

GPi (y = -391.43 + 85.71x, F = 4.86, p = 0.09, R2 = 0.55; Figure 10c) or intermediate GPi

16 17

(y = -121.43 + 35.71x, F = 2.6, p = 0.18, R2 = 0.39; Figure 10d). The human data points

fell within the predicted intervals generated from the nonhuman data for the caudate

nucleus (95% prediction interval: 1.61 – 6.2; expected: 3.91; observed: 4.91; percent

difference (expected – observed/observed): 20%) and the putamen (95% prediction

interval: 0.89 – 8.99; expected: 4.94; observed: 5.14; percent difference (expected –

observed/observed): 4%). Humans possessed higher glia to neuron ratios in both GPi

regions than what would be expected based on the nonhuman data (anteromedial GPi

95% prediction interval: 14.29 – 83.12; expected: 48.71; observed: 134.33; percent

difference (expected – observed/observed): 64%; intermediate GPi 95% prediction

interval: 31.60 – 72.86; expected: 52.23; observed: 99.40; percent difference (expected –

observed/observed): 47%).

Table 1. Mean glia to neuron ratio +/- 1 standard deviation for each species and sampling region.

Species Caudate Putamen GPi Anteromedial GPi Intermediate

Capuchin 1.94 ± 0.24 1.98 ± 0.52 47.31 ± 15.67 64.35 ± 08.69

Macaque 1.27 ± 0.34 1.26 ± 0.33 29.73 ± 08.70 51.17 ± 20.83

Baboon 2.61 ± 0.64 2.10 ± 0.30 48.77 ± 08.62 55.34 ± 24.14

Gorilla 2.60 ± 1.65 2.95 ± 1.86 41.33 ± 17.75 53.50 ± 21.36

Chimpanzee 3.56 ± 0.93 4.86 ± 1.27 49.04 ± 15.90 57.22 ± 20.19

Human 4.91 ± 1.92 5.14 ± 1.40 134.33 ± 92.09 99.40 ± 37.60 18

Figure 7: Glia to neuron ratio in Figure 8: Glia to neuron ratio in the globus the striatum (caudate nucleus & pallidus internus (anteromedial and putamen). Bars represent the intermediate). Bars represent the mean mean and error bars represent and error bars represent one standard one standard deviation. deviation. 19

Figure 9a: Glia to neuron ratios compared with brain size in the caudate.

Figure 9b: Glia to neuron ratios compared with brain size in the putamen. 20

Figure 9c: Glia to neuron ratios compared with brain size in the anteromedial globus pallidus internus (GPi).

Figure 9d: Glia to neuron ratios compared with brain size in the intermediate globus pallidus internus (GPi).

CHAPTER 4

DISCUSSION & CONCLUSION

This represents the first large scale comparative analysis of glia to neuron ratios across primate species within the basal ganglia. The results demonstrate that human possess increased glia to neuron ratios throughout the sampled basal ganglia structures compared to nonhuman primates. The greatest difference was observed in the output structures. The increased metabolic support in the output structures relative to the input structures may be due to the fact that receiving input is a more passive activity and that the relay of information from the striatum to the rest of the basal ganglia is not a metabolically demanding task. However, it appears that a greater energetic demand is associated with the integration and/or the output of information from the globus pallidus for humans. This appears to be a uniquely human trait among primates and may be related to the targets of the information being sent from the globus pallidus. Interestingly, we predicted that differences would be found in the executive loop exclusive to the motor loop, but the results show that humans and chimpanzees share an increase of glia to neuron ratios in the striatum but that humans alone possess increased glia to neuron ratios in the globus pallidus. Linear regression analyses showed human glia to neuron ratios fell within the expected ranges for the striatum, however humans possessed glia to neuron ratios that were 64% and 47% higher than expected for the anteromedial and intermediate

GPi.

21 22

Earlier studies reported an increased glia to neuron ratio for the human neocortex

(Sherwood et al., 2006), but this difference was explained in terms of allometric scaling with brain size. Rilling (2006) argued that humans and other non-human primates aren’t just “allometrically scaled versions of the same design”, meaning that the brains of humans and the great apes aren’t just larger versions of the other non-human primate brains but they are also more specialized. Barger et al. (2014) recently reported that the human striatum was smaller than expected for an anthropoid of our body size. Similar studies are not available for the globus pallidus. But more research studies on the globus pallidus would allow us to determine if the increased metabolic support exists in the absence of an increase in size. Our data revealed that glia to neuron ratio in the striatum increased with brain size. However, glia to neuron ratios in the globus pallidus were higher than expected for overall brain size.

The globus pallidus sends signals back to the cerebral cortex through the thalamus

(Middleton and Strick, 2000). These connections are critical to normal cognitive and motor functions. For example, patients who have lesions that are concentrated to areas of the globus pallidus (output structures) demonstrate impairments in cognition, uncontrollable behaviors, and loss of control over voluntary movement (Strub, 1989;

Laplane et. al., 1989; and Bhatia & Marsden, 1994; Middleton & Strick, 2000). Changes in the pallidal output channels which send information to the thalamus and project back to the cortex may be more significant than the input channels and responsible in causing the cognitive and motor deficits we see in the diseases (Middleton & Strick, 2000;

Hoover & Strick, 1993). 23

The striatum and the globus pallidus internus (GPi) are areas within the basal ganglia that are directly affected by neurodegenerative diseases like Parkinson’s and

Huntington’s diseases. Damage to the motor regions of the basal ganglia (i.e., putamen and intermediate GPi) causes the cognitive [and movement] deficits that we see in the diseases (Dubois & Pillon, 1997). Damage to the caudate and the anteromedial GPi

(executive loop regions) are responsible for the cognitive impairments. For example, individuals with Parkinson’s disease show cognitive impairments in a range of tasks that measure “frontal lobe function,” attention, memory, or visuospatial capacities

(Dairyimple-Alford et. al, 1994; Flowers & Robertson, 1985). They also show the traditional movement dysfunctions such as akinesia, dyskinesia, etc. Although it has been known that damage to the striatum or “input structures” have been known to cause cognitive deficits research focusing on the “output structures” has shown that these structures are involved in both cognitive and motor functions. Trepainer et al. revealed that ventral pallidotomy which is a stimulation surgical therapy for Parkinson’s disease, can cause deficits that affect cognition and cognitive function (1998). Yokochi et al.

(2001) analyzed the relationship between lesion location and the outcome of pallidotomy for Parkinson’s disease and found that lesions in the anteromedial part of the globus pallidus caused changes that resulted in differences in mental function and ability. Okun et. al (2003) also found that patients suffered from “manic behavior” when injuries occurred to the anteromedial globus pallidus internus. 24

Our research revealed that humans had higher glia to neuron ratios in basal ganglia regions relative to nonhuman primates. The most significant differences were observed in the globus pallidus, indicating that there has been an increased metabolic demand associated with output from the basal ganglia in human evolution. The human brain has increased in size compared to overall body size (Falk et al., 2000) compared to other primates. However, this research builds upon the idea that the human brain is not simply a larger version of other primate’s brain, but an organ that has become more specialized and complex in order to support human specific traits such as cognition, language, and other executive functions. With the development of human-specific cognitive and behavioral abilities, we see what appears to be human specific neurodegenerative diseases such as Parkinson’s and Huntington’s. By understanding the areas that are directly involved with these diseases, like the basal ganglia, we can potentially identify how humans differ from other primates and we may be able to determine what makes humans susceptible to these conditions and identify potential targets for therapeutic interventions. 25

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