Motor areas of the frontal lobe

Jarrod Blinch, Mark G Carpenter, Romeo ChuaSchool of Kinesiology, University of British Columbia, Vancouver, Canadajpgblinc@interchange.ubc.ca

“If our brains were simple enough for us to understand them, we'd be so simple that we couldn't.” ― Ian Stewart

As a motor control researcher in cognitive psychology, I use a behavioural approach to study how humans produce movements. Specifically, I record the intricacies of human movements and I use this information to infer how the brain is organised. This is high-level research into human movement; low-level research, for example, would be a neurophysiologist who studies the cellular behaviour of the nervous system. Topics investigated in my field include human information processing, attention, coordination, sensory and central contributions to motor control, etc.

Studies in these areas involve treating the brain like a black box. I can study the stages of information processing without answering where in the brain this processing takes place and how it is accomplished by the vast neural networks. Lately, there has been more interest by behaviouralists to open pandora’s black box to determine neural correlates of behaviour. This has been criticised by some as simply taking behavioural measures that are ‘further up the arm’ but do not result in a better understanding of human performance. You can think of early studies that examined reaction time of a finger movement, later studies that examined electromyography in the hand to calculate premotor time, and now, electroencephalography studies that can determine your reaction time base on the lateralised readiness potential in the cortex.

Regardless of how you feel about this trend in behavioural research, it is becoming increasingly important that researchers in my field understand the progress by neurophysiologist to describe the activity of the cortex. How we might integrate and build on these findings in our research is another question. My understanding of the motor areas of the frontal lobe was poor, despite a few courses in neuroanatomy. I decided to write this review to formalise my investigation into these motor areas. I quickly discovered that the best research came from invasive studies on macaque monkeys and not noninvasive research on humans, so macaques will be the focus of this review. To follow is a basic description of the location of the motor areas of the frontal lobe. I will then give enough background on the central nervous system to understand subsequent descriptions of each motor area. After reviewing each motor area, I will speculate on the complex coordination of all the motor areas that results in a simple reaching movement. One word of warning, there are an unruly amount of abbreviations related to the motor areas. I have tried to minimise their use, but they are often unavoidable. Feel free to refer to the Appendix for a summary of the abbreviations.

Axes of the central nervous system

To locate the motor areas, I will refer to their rostral-caudal and dorsal-ventral locations. The rostral-caudal axis for the cortex begins in the frontal lobe (rostral) and then curves to end in the spinal cord (caudal; Figure 1). As an example, the premotor cortex is rostral to M1. The dorsal-ventral axis is sometimes confusing because it curves with the rostral-caudal axis to be orthogonal to it (Figure 1). Along the spinal cord, dorsal is towards the back; you can think of dorsal pointing to your vestigial dorsal fin. By following the curvature of the rostral-caudal axis, dorsal is towards the top of your skull over the cortex. Some people use dorsal-ventral and superior-inferior or rostral-caudal and anterior-posterior

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interchangeably when referring to cortical structures; I will use only dorsal-ventral and rostral-caudal to avoid confusion.

Figure 1. Axes of the central nervous system. The motor areas of the frontal lobe can be located based on their relative rostral-caudal and dorsal-ventral position. Adapted from Martin (2003).

Location of the motor areas: Macrostructure

We will focus on the motor areas of the frontal lobe (Figure 2). If you start at the junction between the parietal and frontal lobes, denoted by the central sulcus, the first motor area you encounter is aptly named the primary motor cortex (M1). M1 is contained roughly within the precentral gyrus; it is bordered medially by the cingulate sulcus and laterally M1 ends before the lateral fissure. If you continue in the rostral direction, then the next motor areas are the supplementary motor areas (SMAs) and the premotor cortex. The SMAs are located on the medial surface of the frontal lobe, mostly within the sagittal fissure, and the medial border of the SMAs is the cingulate sulcus. The SMAs are comprised of the caudally located SMA proper and the more rostral pre-SMA. There is no macroanatomical landmark demarking the SMAs, but the VCA line has been used in functional imaging studies on humans (Picard & Strick, 1996). The VCA line is a vertical line that is perpendicular to the midline of the anterior commissure (Figure 3; Talairach & Tournoux, 1988).

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Figure 2. Motor areas of the frontal lobe and areas of the posterior parietal cortex. Abbreviations: arcuate sulcus, superior (AS), inferior (AI), and genu (AG), inferior precentral dimple (IPD), cingulate sulcus (CS), central sulcus (C), lateral fissure (L), intraparietal sulcus (IP), premotor cortex, dorsorostral (PMdr), dorsocaudal (PMdc), ventrorostral (PMvr), and ventrocaudal (PMvc), supplementary motor area proper (SMA), pre-supplementary motor area (pre-SMA), primary motor cortex (M1). Adapted from Geyer and colleagues (2000).

Lateral to the SMAs is the premotor cortex. The rostral border that separates the premotor cortex from the prefrontal cortex is the arcuate sulcus. The lateral border is approximately at the level of the inferior precentral dimple (Geyer, Matelli, Luppino, Zilles, 2000). The premotor cortex can be divided into four areas; there are two dorsal areas, the dorsocaudal premotor cortex and the dorsorostral premotor cortex (PMdc and PMdr), and two ventral areas, the ventrocaudal premotor cortex and the ventrorostral premotor cortex (PMvc and PMvr). The two caudal areas (PMdc and PMvc) are separated by the genu of the arcuate sulcus. Slightly rostral to the genu is the approximate border between the caudal (PMdc and PMvc) and rostral (PMdr and PMvr) premotor cortices (Geyer et al, 2000).

For the last three motor areas we need to return to the medial surface of the frontal lobe (Figure 3). Recall that the SMAs and part of M1 are located on the medial wall, within the sagittal fissure. The medial border of these areas is the cingulate sulcus, specifically, as we travel deeper into the sagittal fissure, there is the dorsal bank of the cingulate sulcus, the ventral bank of the cingulate sulcus, the cingulate gyrus, and then the corpus callosum (Figure 4). The cingulate sulcus contains three

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motor areas: the dorsal, ventral, and rostral cingulate motor areas (CMAs). The dorsal CMA is located deep to M1 and SMA proper on the dorsal bank of the cingulate sulcus. Even deeper is the rostral CMA on the ventral bank of the cingulate sulcus. The dorsal and ventral CMAs continue rostrally until approximately the level of the genu of the arcuate sulcus. Rostral to the dorsal and ventral CMAs, spanning both banks of the cingulate sulcus is the rostral CMA (Dum & Strick, 1993; Picard & Strick, 1996).

Figure 3. Motor areas of the medial wall. Adapted from Picard and Strick (1996).

Figure 4. Frontal section of the medial wall. The cingulate sulcus (CS) and the cingulated gyrus (CG) make up the cingulate cortex. Deep to the cingulated cortex is the corpus callosum (CC). Adapted from Dum and Strick (1993).

Cingulate motor areas, dorsal (CMAd), ventral (CMAv), and rostral (CMAr), genu of the arcuate sulcus (AG), corpus callosum (CC), anterior commissure (AC), cingulate sulcus, dorsal (CSd) and ventral (CSv), cingulate gyrus (CG).

An introduction to microstructure

The anatomical landmarks, or macrostructure, discussed above provides approximate borders for the motor areas. More exact borders are defined by the microstructure, which is the neuronal architecture, or cytoarchitecture. Most of the cerebral cortex contains six layers, with layer I on the surface of the cortex and layer VI being the deepest. Throughout the cortex, the relative size and appearance of each layer changes. This was used by Broadmann to divide the cortex into more than 50 areas, now called Broadmann areas (Figure 5; Brodmann, 1909). It was subsequently shown that cortical function is correlated with cytoarchitecture, and so many of the Broadmann areas are still used today. In the motor areas, for example, M1 is Broadmann area 4 and the SMAs and premotor cortex are contained in Broadmann area 6. The major difference between areas 4 and 6 is a gradual decrease in giant pyramidal (Betz) cells in layer V as you travel rostral from area 4 to area 6 (Geyer et al, 2000). Giant pyramidal cells are most likely to form direct corticomotoneuronal connections, which are vital for independent finger movements (Geyer et al, 2000). Another distinction that divides some of the motor areas is if the cortical layers are clearly or poorly separated, which is referred to as the lamination.

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Figure 5. Brodmann areas in the human cortex. Adapted from Martin (2003).

Microstructure provides better borders between the motor areas than macrostructure, but even the microstructure is not exact. The change in cytoarchitecture from one motor area to another is gradual, and so different researchers may decide on different borders. Another area of debate is the number of motor areas. In the 1950s, there were two motor areas, M1 and SMA (Rizzolatti, Luppino, Matelli, 1998). We will describe ten motor areas (M1, SMA proper, pre-SMA, PMdc, PMdr, PMvc, PMvr, CMAd, CMAv, CMAr), but that number is subject to ebb and flow. One example is that M1 may be divisible into two motor areas: rostral M1 and caudal M1 (Roland & Zilles, 1996).

Descending motor pathways

The descending motor tracts connect the cortex and brainstem with muscles (Table 1). These connections allow the motor areas of the frontal lobe to create movements. We will focus on the tracts that begin in the cortex: the lateral corticospinal, the ventral corticospinal, and the corticobulbar tracts. Corticobulbar refers to the motor fibers that project from the cortex to the brainstem (bulb is an old name for the brainstem). Innervations of the corticobulbar tract include muscles of the face, the sternocleidomastoid, and the trapezius. The corticospinal tracts are important for voluntary movements of limb and axial muscles (Blumenfeld, 2010; Kandel, Schwartz, Jessell, 2000; Martin, 2003). These tracts originate in the frontal lobe, the parietal lobe, and the cingulate sulcus. It is estimated that 40 to 60% of the corticospinal fibers originate in the frontal lobe and 40 to 60% originate in the parietal lobe (Figure 6; Geyer et al, 2000). The corticospinal fibers in the frontal lobe originate in the motor areas (M1, SMAs, premotor cortex, CMAs) and terminate mostly in the ventral horn and intermediate zone of the spinal grey matter. This allows these motor areas to directly influence motor behaviour. Interestingly, there are at least as many, or more, corticospinal fibers in the SMAs, premotor cortex, and CMAs as M1, so the rostral motor areas may influence motor behaviour as much as M1 (Geyer et al, 2000).

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Figure 6. Sagittal section of a macaque cortex (left) that shows corticospinal neurons that were retrogradely labeled from the contralateral lumbrosacral enlargement of the spinal cord. The location of the section is shown by the dashed line on the hemisphere (right). Notice the presence of corticospinal neurons in M1 (Brodmann area 4), SMAs and premotor cortex (Brodmann area 6), primary somatosensory cortex (Brodmann area 1, 2, 3a, and 3bv), and secondary somatosensory cortex (Brodmann area 5). Adapted from Murray and Coulter (1981).

The other interesting finding about the corticospinal fibers is that 40 to 60% originate in the parietal lobe. These fibers originate in the primary and secondary somatosensory cortices, the supplementary somatosensory area, and the posterior parietal cortex and terminate mostly in the dorsal horn of the spinal grey matter. The termination in the dorsal horn makes it unlikely that these fibers directly influence motor behaviour. It has been suggested that corticospinal fibers that originate in the parietal lobe modulate the transmission of somatic sensory information (Murray & Coulter, 1981).

The cortcospinal tracts make direct (monosynaptic) and indirect (polysynaptic) connections with alpha motor neurons. We will use the term corticospinal to refer to the direct and indirect connections. The direct connections are also called corticomotoneuronal because of the monosynaptic connection from corticospinal neuron to alpha motor neuron. These corticomotoneuronal connections are most likely to originate from giant pyramidal (Betz) cells (Geyer et al, 2000). Corticomotoneurons rarely connect to just one muscle but rather a small group of muscles, which may even involve movements at different joints. This grouping allows task-specific combinations of movements, for example, activating the muscles needed for a precision grip. Less individuated or multijoint movements (like a power grip) are likely controlled by the indirect connections of the corticospinal tracts. These indirect corticospinal connections project to divergent interneurons in the spinal cord and synapse with several alpha motor neurons. Corticospinal connections can have excitatory and inhibitory effects on motor neurons. Inhibition is mediated by Ia inhibitory interneurons, the same neurons involved in the monosynaptic stretch reflex (Kandel et al, 2000).

Corticomotoneuronal fibers are vital for independent finger movements, and the dexterity of different animals (and within a species) is determined by the number of corticomotoneuronal projections. Humans and great apes are more dexterous than macaques, and they also have more direct corticomotoneuronal connections (Geyer et al, 2000). The relationship between dexterity and the corticospinal tracts is shown by the loss in individuated finger movements after cutting the corticospinal and corticomotoneuronal fibers in a monkey. After recovery, dexterous finger movements are impossible but, interestingly, all other movements are intact (with a decrease in movement speed). These movements are made possible by cortical connections to the intact descending motor tracts in the brainstem (Kandel, Schwartz, & Jessell, 2000).

Table 1. Descending motor tracts of the cortex and brainstem (Blumenfeld, 2010; Kandel, Schwartz, Jessell, 2000; Martin, 2003).

Tract Origin FunctionCortexLateral corticospinal Brodmann areas 6, 4, 1, 2, 3, 5,

7, 23, 24Voluntary movements of contralateral limb muscles

Ventral corticospinal Brodmann areas 6, 4 Voluntary movements of bilateral axial muscles

Corticobulbar Broadman areas 6, 4, 1, 2, 3, 5, 7, 23, 24

Voluntary movements of cranial muscles (bilateral and contralateral)

BrainstemRubrospinal Red nucleus, magnocellular Voluntary movement of

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division contralateral upper limb muscles (uncertain function in humans, may be replaced by the corticospinal tracts)

Lateral vestibulospinal Lateral vestibular nucleus Balance, extensor musclesMedial vestibulospinal Medial and inferior vestibular

nucleiHead position and neck muscles

Pontine reticulispinal Pontine reticular formation Automatic posture and gait related movements, influences muscle tone

Medullary reticulospinal Medullary reticular formation

Tectospinal Deep superior colliculus Coordinates contralateral neck and eye movements (uncertain function in humans)

Posterior parietal cortex (PPC) and parietofrontal circuits

The posterior parietal cortex is a dorsal section of the parietal lobe that begins caudal to the primary somatosensory cortex (Figure 1). Its classic role is the integration of visual, auditory, and somatosensory information for perception and attention (Martin, 2003). The posterior parietal cortex also connects with the motor areas of the frontal lobe. These parietofrontal circuits form a series of specialised circuits working in parallel to transform sensory information into action (Rizzolatti et al, 1998). Each motor area has unique connections with the posterior parietal cortex; there is typically one predominant connection and several additional connections. These are listed in Table 2 and displayed in Figure 7. Additional connections will be shown in parentheses; for example, PMvr receives connections from VIP (PF, PEip), or simply VIP (PF, PEip) PMvc.

Table 2. Parietofrontal circuits formed by connections between the posterior parietal cortex and the motor areas of the frontal lobes. Adapted from Rizzolatti et al (1998).

Motor area PPC connections Primary parietofrontal functionPredominant Additional

M1 PE Current estimate of the body’s location to control movements

SMA proper PEci PE, PFG Global aspects of movementsPre-SMA PFGPMdcd PEc, PEip PFG Somatosensory information for movement preparation

and online controlPMdcvr MIP V6A, PFG Somatosensory and visual information for movement

preparation and online controlVentral PMdr PGm V6A, PG Response selection for conditional stimulus-response

tasksSEF LIP Saccades that require complex programmingPMvc VIP PF, PEip Planning movements in peripersonal spacePMvrc PF AIP Representing actions internallyPMvrab AIP PFG Transforming object properties into grasping movementsCMAd ? ? ?CMAv ? ? ?CMAr ? ? ?

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Figure 7. Parietofrontal motor projections from the convexity and medial bank of the superior parietal lobule (A) (inferior parietal lobule and occipital lobe removed), the fondus and the lateral bank of the intraparietal sulcus (B) (occipital lobe removed and intraparietal sulcus opened), and the convexity of the inferior parietal lobule (C). Adapted from Geyer (2000).

There is a simple organisational scheme to the visual and somatosensory information in the posterior parietal cortex. It is divided into four subareas, first, the superior parietal lobule and the inferior parietal lobule, divided by the intraparietal sulcus (IP; Figure 2). These areas are also roughly divided into rostral and caudal subareas. The predominant type of sensory information in each subarea is shown in Table 3. This can be used, for example, to infer that a PPC circuit that originates in the caudal inferior parietal lobule (such as the LIP to the dorsal PMdr) involves visual information.

Table 3. The location of visual and somatosensory information in the four subareas of the posterior parietal lobe.Rostral Caudal

Superior parietal lobule Somatosensory VisualIntraparietal sulcus

Inferior parietal lobule Somatosensory & visual Visual

Thalamus

The thalamus is the structure that resembles two scoops of ice cream sitting on top of the ice cream cone that is the brainstem. It is an important relay center for the cortex; somatosensory pathways and subcortical structures form reciprocal connections with thalamic nuclei before heading to

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the cortex (Blumenfeld, 2010). The major sections of the thalamus and their cortical projections are shown in Figure 8. We are interested in the thalamus because of the connections from the basal ganglia and the cerebellum to the motor areas in the frontal lobe. Acronyms for the thalamic nuclei are listed in Table 4 and the circuits that I will detail are shown in Table 5. A few notes: the pallidum includes the globus pallidus and an area just ventral called the ventral pallidum, the deep cerebellar nuclei are the dentate, emboliform, globose, and fastigial (don’t eat greasy foods), area X borders the ventral anterior and ventral lateral areas (Olszewski, 1952; van Donkelaar et al, 1999).

Figure 8. The major division of the thalamus and the cortical regions that they connect to (top). Sagittal sections through a macaque monkey thalamus that shows most of the thalamic nuclei listed in Table 4 (bottom). The first section (bottom-left) is 3.5 mm lateral to the midline, and the second section (bottom-right) is 5.5 mm lateral to the midline. Also shown are the lateral dorsal nucleus (LD) and the reticular thalamic nucleus (R). Nucleus medialis dorsalis (MD) is shown in the above image and is labeled as the medial dorsal nucleus. Adapted from Martin (2003) and van Donkelaar et al (1999).

Table 4. Names and abbreviations of the thalamic nuclei involved with motor areas of the frontal lobe.Thalamic nucleus

Abbreviation NameMD nucleus medialis dorsalisVAmc nucleus ventralis anterior magnocellularisVApc nucleus ventralis anterior pars parvocellularisVL nucleus ventralis lateralisVLc nucleus ventralis lateralis pars caudalis

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VLo nucleus ventralis lateralis pars oralisVPLo nucleus ventralis posterolateralis pars oralisX area X, Olszewski (1952)

Table 4. The motor areas of the frontal lobe are connected with the basal ganglia and the cerebellum via the thalamus.Caudate, putamen VL M1Putamen, pallidum VLo SMA proper, PMdc, PMvcPallidum VLo CMAdPallidum VLc CMAvDeep cerebellar nuclei VLc CMAvCaudate, cerebellum VApc pre-SMA, PMdrCerebellum X PMvr

Why study monkeys?

Much of our understanding of the motor areas of the frontal lobe is the result of experiments on macaque monkeys. Invasive animal research is fundamental to understand the brain as it is the microstructure of the brain -- not the macrostructure -- that is correlated with function (Geyer et al, 2000). Functional imaging studies in humans are currently limited to macroanatomical landmarks, so invasive studies on animals are required. The research in this review is based on macaque monkeys. Almost all of the findings in this review are from macaques. It will be explicitly stated when a finding is from human participants (for example, the human homology sections). Macaques are a species of Old World monkeys, which means they originated from Africa and Asia (New World monkeys are from Central and South America; “Old World monkey,” 2011). Evolutionary wise, the great apes, specifically chimpanzees, are the closest extant relatives to humans (“Ape,” 2011). There are several reasons why apes are not typically used for invasive brain research. Great apes are large, strong, can be aggressive, and require a lot of room. Using apes for research is so expensive that they are typically tested for several years. Most of the research described in this review involves single unit recordings of neurons or injecting tracers into the brain and then subsequent histochemical staining. Both types of research, unfortunately, involve sacrificing the macaque participant. Macaques are used because they are easier to care for than great apes and sacrificing them is considered more ethical because they are less human-like than great apes.

Macaques are still similar to humans, and that is why we are interested in their brains. Figure 9 shows the motor areas of the frontal lobe in an Old World monkey (left) compare to humans (right). Both brains have a similar mirrored c shape formed by the end of the motor areas in the frontal lobe. Like humans, macaques are highly social and live in supportive families (Figure 10, left). Macaques are caring and have been known to adopt other animals in need, such as the motherless kitten in Figure 10 (right), so is it ethical to sacrifice macaques for research? Is it fair that we have an easier time sacrificing animals that are less human-like (macaques vs. chimps) or less cute (calves [veal] vs. kittens)? Does it matter if the research is trying to cure cancer or investigate the fundamentals of neural activity? These are important moral questions and we should carefully consider the ramifications of research. Even though I am a behavioural researcher and test only humans, I am still relying on animal research to understand the nervous system. As you read this review, keep in mind that this knowledge has cost the lives of thousands of macaques.

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Figure 9. A comparison of the shape of the motor areas of the frontal lobe in a New World monkey (left) and humans (right). Adapted from Geyer et al (2000).

Figure 10. Macaques exhibit human characteristics, for example, enjoying a hot spring (an onsen) with friends in Japan (left) and caring for a motherless kitten (right).

Primary motor cortex (M1)

M1 has a long history of research and is better understood than the other motor areas of the frontal lobe. I will detail some of this fundamental research, but for those unfamiliar with M1, I recommend Chapter 38 (Voluntary movement) in Kandel et al. (2000) and Chapter 9 (Cerebral cortex) in Rothwell (1994). One warning, the discussion on the other motor areas of the frontal lobe in these books is out-of-date.

M1 is characterised by a complete somatotopic representation of body movements and the associated motor homunculus (Penfield & Rasmussen, 1952). Each hemisphere of M1 controls the

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contralateral side of the body (save for the axial muscles that have bilateral projections from each hemisphere). Early studies on the motor homunculus led to the belief that M1 was the final common pathway for voluntary movements and that M1 acted as cortical keyboard with a specific key for each muscle. Later studies with intracortical microstimulation of M1 showed that an individual muscle can be activated from a range of sites in M1 and that stimulation rarely activates a single muscle (Kandel et al, 2000). It seems that M1 is more sophisticated than a cortical keyboard; I will explain the current understand of how M1 controls voluntary movements in the Function section.

The precentral gyrus, Broadmann area 4, is home to M1. Its unique microstructure is identified by prominent giant pyramidal cells in layer V, no layer IV, poor lamination, and low cell density. M1 has the most corticospinal fibers of all the motor areas. This gives it the greatest ability to influence voluntary movements (Geyer et al, 2000).

Connectivity

Here are a few notes that will be useful for all the connectivity diagrams. These diagrams illustrate the connectivity of the shaded motor area (in this case, M1). The motor areas surrounding the shaded motor area are all connected with that area, so CMAv, CMAd, SMA proper, PMdc, PMvr, and PMvc are all connected with M1. A motor area with a gray box instead of a black box means that it has minor connections with the shaded motor area. The descending efferents are show with orange arrows, subcortical circuits (mostly from the basal ganglia, cerebellum, or both) are shown with green arrows. Purple arrows show inputs from areas such as the posterior parietal cortex, thalamus, and prefrontal cortex.

There are interconnections between M1 and all the other motor areas of the frontal lobe except pre-SMA, PMdr, and CMAr, which are connected with the prefrontal cortex instead (Geyer et al, 2000). M1 in each hemisphere is connected by callosal afferents. These pathways have been implicated in interhemispheric inhibition/excitation (van der Knaap & van der Ham, 2011) and bimanual movements (Swinnen & Wenderoth, 2004). The primary somatosensory cortex (SI) is also connected with M1. This allows information about sensory receptive fields to be used by M1 for controlling movement (Kandel et al, 2000).

Function

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M1 is activated immediately preceding muscle activity as well as hundred of milliseconds before activation of the muscles. This early activity in M1 may reflect movement preparation, but it could also be the result of executing anticipatory postural adjustments that precede voluntary movements (Kandel et al, 2000). The time course of activation of the motor areas in the frontal lobe typically follow a rostral to caudal pattern with M1 being the last area activated. This is shown by the readiness potential (also known as the Bereitschaftspotential), an event-related potential that precedes voluntary movements by one to two seconds. The readiness potential begins with activation in the pre-SMA and then travels caudal to the SMA proper and then M1 (Deecke, 1990).

As discussed earlier, activity in M1 is not as simple as a cortical keyboard with a one-to-one relationship between neuronal activity and individual muscles. There are correlations between activity in M1 and the dynamic and kinematic parameters of movement. One such relationship is between the force of the movement and amount of activation in M1 (Kandel et al, 2000). More detailed analysis of the activity in M1 has shown that the direction of the movement is coded in M1 (Georgopoulos, Kalaska, Caminiti, Massey, 1996). Each cell in M1 has a preferred movement direction. If you multiply the activation level of the cell by its preferred direction, then you have a vector that represents one vote towards the movement’s direction. The actual direction is determined by summing all the individual vectors into a population vector that points in the direction of the movement. M1, therefore, codes the direction of the movement, which is a higher level parameter of the movement. M1 also codes low level parameters of the movement, such as muscle forces. The ability for M1 to code low- and high-level parameters of the movement distinguishes M1 neurons from alpha motor neurons (Kandel et al, 2000).

The function of M1 is also related to its connection to PE in the posterior parietal cortex. PE is a somatosensory area that is mostly involved with proprioception. It responds to combinations of joint positions or joint and skin stimuli that provide an egocentric coding of the body’s position in space. It is believed that this provides M1 with a current estimate of the body’s location in order to control movements (Geyer et al, 2000).

Human homology

The cytoarchitecture of M1 in the precentral gyrus is very similar in humans and macaques. M1 was labeled as area 4 by Broadmann (1909) and areas 4a, 4b, and 4c by Vogt and Vogt (1919). Recently, M1 has been divided into rostral and caudal (or anterior and posterior) subareas in humans and monkeys (Geyer et al, 2000). Representations of the digits have been shown in the rostral and caudal subareas, but face and limb representations have yet to be mapped (Roland & Zilles, 1996).

Supplementary motor areas (SMAs)

The SMA proper and the pre-SMA were original viewed as a single motor area called the supplementary motor area (SMA). It was referred to as supplementary because, in addition to M1, there is a complete representation of body movements. Rostral to M1 on the medial surface is the SMA proper. The SMA proper, like M1, is poorly laminated; this is used to define the border between the SMA proper and the pre-SMA as the pre-SMA is clearly laminated (Geyer et al, 2000). The connectivity of the SMA-proper and the pre-SMA is also unique.

Connectivity

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The SMAs have 10 to 20% of the corticospinal fibers in the frontal lobe (Dum & Strick, 1991). They are connected with the other motor areas of the frontal lobe, including the cingulate motor areas in the cingulate cortex. Only the SMA proper is connected with M1, which gives it more direct access to motor effectors than the pre-SMA. The pre-SMA is unique in that it has cortical afferents from the prefrontal cortex and no predominant input from the posterior parietal cortex (similar to PMdr and CMAr). The basal ganglia are connected to both SMAs with unique circuits through the ventral thalamus. The pallidum, which connects to the SMA proper, includes the globus pallidus and an area just ventral called the ventral pallidum. The cerebellum sends output to the pre-SMA and not the SMA proper (Geyer et al, 2000).

The SMA proper sends descending projections to the corticospinal tracts (lateral and ventral) and the corticobulbar tract. The pre-SMA sends descending efferents to the corticobulbar tract1 (Geyer et al, 2000) and sparse projections to the corticospinal tract for movements of the arm (Luppino et al, 1994; Nachev et al, 2008).

Function

SMA proper has a complete representation of the body, but the pre-SMA has a representation of only the arms. This difference in representations has been shown with intracortical microstimulation. The basic change in microstimulation as you travel rostral from M1 to the SMAs or the premotor cortex is that the excitability decreases, the threshold required to induce a movement increases, and the complexity of the induced movement increases. The decrease in excitability and the increase in stimulation threshold are likely related to the decreasing density of giant pyramidal cells as you travel rostral from M1. The movements induced from SMA proper are similar to those from M1 in that they are fast and short lasting but they have a higher stimulation threshold. There are more proximal movements than distal movements, 60% of the movements are simple and 30% are complex, and there is poor spatial separation between areas of the body. The pre-SMA differs from the SMA proper in that

1 In one study, retrograde tracers were injected into corticobulbar axons in the medial tegmentum of the medulla. These were either into the medial reticular formation (between motor nucleus V and VI) or extending from the surface of the pontomedullary junction to the basal pons (Keizer & Kuypers, 1989). Therefore, the corticobulbar axons that originated in pre-SMA could have travelled to motor nuclei V, VI, VII, IX, X, XI, or XII.

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simulation thresholds are higher and instead of complex movements, 40% of the movements are slow displacements of the limbs (Geyer et al, 2000).

Another caudal-to-rostral trend from M1 to SMA proper to pre-SMA involves the density of interhemispheric callosal connections. There is an increase in the density of callosal connections as you travel rostral from M1; M1 is poorly interconnected, SMA proper has some interconnections, and pre-SMA has substantial contralateral connections. These three areas are typically activated in a rostral-to-caudal order, so the density of connections suggests that earlier phases of movement preparation require greater interhemispheric interaction compared to later phases of preparation (Liu et al, 2002).

Single unit recording studies have also found differences between the SMA proper and the pre-SMA. The SMA proper responds to mainly somatosensory stimuli and the neural activity is mostly time locked to the onset of movement. The pre-SMA responds to visual stimuli and its activity occurs during the preparatory period before movement onset; for example, a visual precue about an impending movement will result in activation of the pre-SMA that reflects movement preparation (Geyer et al, 2000).

The SMAs each have a unique cortical circuit that contributes to their function: the SMA proper has a predominant input from the PEci of the posterior parietal cortex (Figure 5A); the pre-SMA does not have a predominant input from the posterior parietal cortex but does have inputs from the prefrontal cortex. The PEci is often referred to as the supplementary sensory area because it has a complete somatosensory map of the body. It is hypothesised that this somatosensory map allows the SMA proper to control global aspects of movements (Rizzolatti et al, 1998). One possibility is that the SMA proper is involved in anticipatory postural adjustments that occur immediately prior to voluntary movements. The input to the SMA proper from the basal ganglia may also be important for these postural adjustments (Massion, 1992).

Pre-SMA does not have a predominant input from the posterior parietal cortex, so it is unlikely to be directly involved with the transformation of sensory information into action. The prefrontal input to pre-SMA suggests that the pre-SMA may be a supramotor control center that triggers movements prepared in other motor areas when an action is called for by external contingencies or internal motivational factors. This is supported by pre-SMA activity that is correlated with whether an object can be grasped; for example, some neurons begin to discharge when an object that is too far away to grasp is moved closer into peripersonal space (Rizzolatti et al, 1998). The view of the pre-SMA as a supramotor control center fits with the finding from human functional imaging that the pre-SMA is activated by complex motor task that place increased processing demands on response selection. The SMA proper, in comparison, is recruited by relatively simple movements, like a finger flexion in a simple reaction time task (Picard & Strick, 1996).

There has been debate over the role of the SMAs and the premotor cortex in self-initiated and eternally cued movements. It was originally thought that the SMAs were involved in only self-initiated movements and the premotor cortex was involved in only externally cued movements. It has been shown that the SMAs and the premotor cortex are involved in both types of movement initiation, but there may be a relative distinction between the areas (Tanji, 1996).

One challenge with the SMAs is that they have been associated with a plethora of functions. They have been linked to self-initiated and externally triggered movements, movement sequences, learning, cognitive control, bimanual movements, anticipatory postural adjustments, and Parkinson’s disease (Jacobs et al, 2009; Nachev et al, 2008). It has been suggested that all of these functions may be linked by the complexity of their condition-action associations (Nachev et al, 2008). However, there seems to be as many theories on the function of the SMAs as there are SMA researchers.

Human homology

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The unique cytoarchitecture of the SMA proper and the pre-SMA is strikingly similar to the medial portion of Brodmann area 6 in humans. Vogt and Vogt (1919) followed up Broadman’s work and divided area 6 into subareas. The medial portion of area 6 was divided into medial 6aα and 6aβ (Figures 10 & 11), which are likely the human homology of the SMA proper and the pre-SMA (Geyer et al, 2000).

Premotor cortex

The premotor cortex consists of four areas that are named after their rostral-caudal and dorsal-ventral positions. Three of these areas can be divided into two subareas. The PMdr is divided into dorsal and ventral subareas. The dorsal PMdr is also called the supplementary eye field (SEF), which is involved in saccades (Schlag & Schlag-Rey, 1987). The PMdc is divided into a subarea by the superior precentral dimple (PMdcd) and a ventrorostral subarea (PMdcvr). The PMvr can be divided into subareas on the dorsal convexity (PMvrc) and on the caudal bank of the inferior arcuate sulcus (arcuate bank, PMvrab) (Rizzolatti et al, 1998).

The division of the rostral and caudal premotor areas is based on the microstructure. The caudal premotor areas (PMdc and PMvc) are poorly laminated like M1 and SMA proper, and the rostral premotor areas (PMdr and PMvr) are clearly laminated and have a prominent layer V (Geyer et al, 2000). The division of the dorsal and ventral areas, and the subareas, is based on the distinct afferent and efferent connections.

Connectivity

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PMdc, PMvc, and PMvr have connections with M1. This connection in PMvr is isolated to a small section of PMvrab. The remaining premotor area, PMdr, does not connect with M1. It is similar to the pre-SMA in that it connects with the prefrontal cortex instead of M1. Two other similarities are that the ventral PMdr and the pre-SMA do not receive input from the posterior parietal cortex and that they form circuits with the caudate and cerebellum. PMdc and PMvc are similar to the SMA proper in that they form circuits with the putamen and pallidum. The last subcortical circuit of note is a connection from the cerebellum to PMvr (Geyer et al, 2000). Ventral PMvc has descending efferents to the brainstem nuclei that control the orofacial muscles. These include the trigeminal maxillary, facial, and hypoglossal cranial nerves.

Function

PMdcLike M1 and SMA proper, PMdc is somatotopically organised and movements can be evoked

with electrical stimulation (Geyer et al, 2000). Single unit recording studies have shown neurons that discharge with movement onset and in advance, which likely have a role in movement preparation. These two categories of neurons are referred to as movement-related and signal-related neurons. Signal-related neurons fire when a visual stimulus precues a movement that will be subsequently performed (Rizzolatti et al, 1998).

The PMdc is divided into two subareas based on connections with the posterior parietal cortex. The first area is PMdcd, which is connected with PEip and PEc. Somatosensory stimuli and arm movements activate PEip (Rizzolatti et al, 1998). Activation during arm movements may be related to the corticospinal projections that originate in PEip (Geyer et al, 2000). Groups of neurons that respond to somatosensory stimuli form tactile receptive fields on the arms. PEip also contains visual and bimodal receptive fields that are related to the tactile fields. The visual fields surround the tactile fields, and the visual fields expand during movement preparation, which is similar to action-centered attention (Tipper et al, 1992). There is little research on PEc, but it is connected with PE and then M1. It is believed that

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the PEip and PEc to PMdcd circuit is involved in the analysis of somatosensory information for movement preparation and online control of the arms and legs (Rizzolatti et al, 1998).

The other parietal circuit connects MIP (V6A) to PMdcvr. There is little research on MIP, but neurons in V6A respond to visual stimuli and movements of the eye or arm. It has been conjectured that the MIP (V6A) to PMdcvr circuit has a similar role as the PEip and PEc to PMdcd circuit, with the addition that somatosensory and visual information contribute to preparation and control. Support for the contribution of both these circuits to online control comes from studies on optic ataxia (Rizzolatti et al, 1998). Optic ataxia is a disorder that results in a deficit to online control, specifically during visually guided hand movements (Kolb & Whishaw, 2003). It is a result of damage to the superior parietal lobule, which includes PEip, PEc, MIP, and V6A as well as PE.

PMdrElectrical stimulation of ventral PMdr rarely evokes movements, which fits with the decrease in

giant pyramidal cells as you travel rostral from M1 (Geyer et al, 2000). Stimulation of SEF (dorsal PMdr) can result in saccades that either move the eyes to a target or focus the eyes on a target. There are more visually responsive neurons in PMdr than PMdc. The signal-related neurons in PMdr are unique from those in PMdc in that they do not require a subsequent movement to the stimulus (Rizzolatti et al, 1998). As with PMdc, PMdr is divided into two subareas based on unique circuits with the posterior parietal cortex. The first circuit is PGm to ventral PMdr; PGm is richly connected with PG and V6A and discharges during eye and arm movements. This circuit is integral in response selection for conditional stimulus-response association tasks, which is supported by lesion studies. A lesion to ventral PMdr that extended to rostral PMdr prevented the selection of arbitrary goal-directed movements to coloured stimuli. Interestingly, the selection of directly-cued goal-direct movements remained intact (Halsband & Passingham, 1982).

LIP connects to SEF (dorsal PMdr), and it encodes signals related to saccades and visual memory. This visual memory is stored in an eye-centered frame of reference and is updated following eye movements. This may allow LIP to contribute to a stable internal representation of the visual scene. The LIP to SEF circuit may be important for saccades that require complex programming, such as saccades that must also account for movements of the head or body (Geyer et al, 2000).

PMvcPMvc has a somatotopic organisation with representations for movements of the arm, neck,

face, and mouth (Rizzolatti et al, 1998). Mainly proximal movements can be evoked by electrical stimulation. Compared to M1, the evoked movements are more complex and require higher stimulation thresholds (Geyer et al, 2000). Single unit recording studies have found tactile neurons and visual-tactile bimodal neurons. The tactile receptive fields are on the arm, upper body, and face. The visual fields surround the tactile fields in peripersonal space. Most of the visual fields are coded in a body-parts-centered frame of reference and do not change following eye movements (Rizzolatti et al, 1998).

VIP to PMvc is the only predominant connection with the posterior parietal cortex. VIP receives visual information from the dorsal stream and somatosensory information from PEc and PFG. This results in tactile receptive fields that are mostly on the face with surrounding visual fields in peripersonal space (Rizzolatti et al, 1998). VIP is coded with head-centered frame of reference, unlike the eye-centered reference in the nearby LIP (Geyer et al, 2000). The emphasis of peripersonal space in this circuit is likely involved in planning movements in this area (Rizzolatti et al, 1998).

PMvrPMvr is somatotopically organised, but movements are more difficult to evoke than in PMvc

(Geyer et al, 2000). Single unit records have shown that the neurons discharge during goal-directed

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actions, particularly those performed with the hand or mouth, such as grasping, holding, tearing, and manipulating. Specific neurons will fire at different phase of the grasp (Rizzolatti et al, 1998), and similar grasps will result in the same activity regardless of the object (Geyer et al, 2000). PMvr is divided into PMvrab and PMvrc by unique posterior parietal circuits. These areas are differentiated by their response to object presentation and subsequent actions. PMvrab neurons fire with object presentation even if there is no subsequent action. Neurons in PMvrc require an object as well as an action, but the action can be performed or witnessed.

These are referred to as mirror neurons, and they are active during self-produced movements and observed movements (Rizzolatti et al, 1998). The majority of mirror neurons are active during a specific observed or executed action (Rizzolatti et al, 2001). Mirror neurons are not simply activated by visual feedback of a self-produced or observe movement as the same neurons fire during movements without vision (Geyer et al, 2000). Mirror neurons also fire if the action is recognised but the final grasp is hidden from the observer. This was shown in a study where an object was placed on a table in plain sight and then hidden from view of the monkey. The monkey’s mirror neurons were still activated when they observed someone reaching to the object, which suggests mirror neurons are involved action recognition. The mirror neurons in PMvrc form a circuit with PF in the posterior parietal cortex. PF neurons respond to somatosensory and visual information, but they also act like mirror neurons in that many are active during observed or executed actions. Some PF neurons respond to observed actions but not to the same self-produced movements. These are similar to neurons in the superior temporal sulcus that discharge to the observation and not production of biological movements. The PF to PMvr c circuit may allow for action recognition and imitation by representing actions internally (Geyer et al, 2000; Rizzolatti et al, 1998).

The other posterior parietal circuit is from AIP to PMvrab. Most AIP neurons discharge during grasping movements with the hand or fingers. These neurons are motor-dominant, visual-dominant, and visual and motor. Motor-dominant neurons respond to a specific type of grasp regardless of the object’s location (Rizzolatti et al, 1998). Many visual-dominant neurons respond to objects with similar properties (Rizzolatti, 2001), and visual and motor neurons prefer the same object for fixation and grasping (Geyer et al, 2000). It is hypothesised that the AIP to PMvrab circuit transforms object properties into appropriate grasping movements (Rizzolatti et al, 1998). This may be accomplished with a network that begins with activation of the inferotemporal cortex to determine the meaning of the object. The inferotemporal cortex is connected with AIP where the object’s meaning is combined with its properties. These object affordances are then passed to PMvrab where multiple grasps are prepared. Connections between PMvrab and pre-SMA are then used to select the appropriate grasp (Rizzolatti et al, 2001).

The ability of the AIP to PMvrab circuit to transform object properties into appropriate grasps has been studies by inactivation of this circuit. If either area is inactivated, then the reaching movement is preserved but the preshaping of the hand during the reach is disrupted. A grip can be achieved but only after tactile exploration of the object. Inactivation of AIP in one hemisphere results in deficit in the contralateral hand. Interestingly, inactivation of PMvrab in one hemisphere results in a bilateral deficit; this implies that PMvrab exerts a bilateral influence on grasping movements (Rizzolatti et al, 2001).

Human homology

The human homologies of the subareas of the macaque premotor cortex are more difficult to establish than the SMAs. One challenge is that humans do not have an arcuate sulcus that divides the premotor cortex from the prefrontal cortex. Superior 6aα and 6aβ in humans may be the homologies of PMdc and PMdr, and inferior 6aα may be the homologue of PMvc (Figure 11). PMvr may have evolved in humans into Brodmann areas 44 and 45 (Geyer et al, 2000). These two areas are also referred to as

19

Broca’s area, which is involved in speech production (Martin, 2003). Area 44 may be the homologue of PMvr as well as being part of Broca’s area (Geyer et al, 2000). Another difference in humans is that SEF is located between the pre-SMA and SMA proper (Figure 12) and not the dorsal aspect of PMdr (Figure 2; Nachev et al, 2008).

Figure 11. Potential human homologies of the premotor cortex. Motor areas in the frontal lobe with the same colours as Figure 2 may be homologies. Adapted from Geyer et al (2000).

Cingulate motor areas (CMAs)

The CMAs are relatively underexplored compared to the other motor areas of the frontal lobe. This has resulted in intriguing research in this new frontier to determine the function of the CMAs. This research is new but the CMAs, part of the allocortex, are phylogenetically older than the other motor areas in the neocortex. The CMAs are part of the limbic lobe, which is involved with emotion, learning, and memory (Martin, 2003). Part of the limbic lobe is the cingulate cortex. The superficial cingulate sulcus and the deeper cingulate gyrus form the cingulate cortex (Figure 4). The three CMAs are located within the cingulate sulcus: the dorsal, ventral, and rostral CMAs (CMAd, CMAv, and CMAr; Figure 3). Although situated in the limbic lobe, the CMAs are richly interconnected with the motor system. In contrast, the cingulate gyrus is connected with the limbic system (Picard & Strick, 1996).

The CMAs are distinct from the other motor areas, even the nearby SMAs, with unique cytoarchitecture. In terms of Broadmann areas, CMAd is a subfield of area 6 (below the SMAs), CMAv a subfield of area 23, and CMAr a subfield of area 24 (Figure 5). There are corticospinal neurons in the CMAs, in fact, the CMAs contain 21% of the corticospinal neurons in the motor areas of the frontal lobe (M1, SMAs, premotor cortex, CMAs). This is a larger percentage of frontal corticospinal neurons than the SMAs and 40% as many as M1. The CMAs also contain more corticospinal neurons that connect to the arm than the SMAs and 75% as many as M1. These connections allow the CMAs to directly control movements at least as well as the SMAs. However, giant pyramidal cells are rare in the CMAs. The typical pattern of a decrease in the density of corticospinal neurons as you travel rostral from M1 exists in the CMAs. If we consider only the corticospinal neurons in the CMAS, then the relative percentages of corticospinal neurons in the CMAs are as follows: CMAd 49%, CMAv 32%, and CMAr 19% (Dum & Strick, 1993).

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Connectivity

CMAdThalmus: VLo CMAd (Holsapple & Strick, 1989)

pallidum VLoPPC: ?Cortical connections: M1, SMAs, CMAsDescending efferents: many corticospinal

CMAvThalmus: VLc CMAv (Holsapple & Strick, 1989)

pallidum VLcDeep cerebellar nuclei VLc CMAv

PPC: ?Cortical connections: M1, prefrontal cortex, SMAs, CMAsDescending efferents: corticospinal

CMArThalmus: ?PPC: ?Cortical connections: prefrontal cortex, SMAs, CMAsDescending efferents: some corticospinal

The CMAs are richly interconnected with each other and the SMAs. CMAd and CMAv are similar to SMA proper in that they are all connected with M1. CMAv and CMAr are connected with the

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prefrontal cortex, which is similar to the pre-SMA. The connections with the posterior parietal cortex have yet to be mapped, but it is believed that each CMA forms a unique parietofrontal circuit. The CMAs also has subcortical connections with the basal ganglia and the cerebellum (Dum & Strick, 1993; Holsapple & Strick, 1989).

Function

Each CMA has a representation for the arms and legs. The face is represented in only CMAr; this region projects to the face representation in M1. There is a lower probability of evoking movements with intracortical microstimulation and a higher stimulation threshold is required in CMAd and CMAv than M1 or the SMAs (Dum & Strick, 1993). Evoked movements are rare in CMAr, which correlated with the lower density of corticospinal neurons (Picard & Strick, 1996). Like M1, the evoked movements are contralateral to the stimulated hemisphere (Dum & Strick, 1993).

Single unit recording studies have shown that relatively simple and complex movements activate the CMAs. CMAd is selectively activated by movement sequences that are overlearned, which may indicate a role in preparing or executing sequential movements (Stick, Dum, Picard, 1998). Movement preparation may also occur in CMAr, as it is active in the period of time after a self-paced movement is cued and before it is initiated (set-related activity; Dum & Strick, 1993).

Human homology

The human cingulate sulcus contains a caudal cingulate zone (CCZ) and a rostral cingulate zone (RCZ; Figure 12). Functional imaging studies have shown greater activation of CCZ with relatively simple movements and greater activation of RCZ with complex movements. RCZ has been implicated in movement selection and the willful generation of movements. It is also activated with the prefrontal cortex and has been divided into anterior and posterior subareas (RCZa, RCZp). RCZa may be the homologue of CMAr, which is connected with the prefrontal cortex. CCZ and CMAd may be homologues, as they both do not connect with the prefrontal cortex. CMAv is unique in that it connects with M1 and the prefronal cortex; a homologue for this area has yet to be established.

Figure 12. The cingulate zones in the human cingulate sulcus: anterior and posterior rostral cingulate zones (RCZa and RCZp) and caudal cingulate zone (CCZ). Adapted from Replace with Nachev et al (2008).

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Complex coordination of the cortical motor areas

This reviewed focused on one motor area at a time to incrementally build our understanding of the motor areas of the frontal lobe. This organisation inadvertently minimised the complex coordination of the motor areas that occurs for even relatively simple movements. This final section will apply our knowledge of the motor areas to a reaching movement of a macaque. I will estimate the sequence of activation of the motor areas based on everything that we have discussed.

Imagine a macaque sitting in a chair at a desk. On the desk, within reach, are two golf balls. There is a yellow coloured golf ball to the left and a white golf ball to the right. The monkey has been trained to reach for and pick up the golf ball identified by a visual imperative stimulus. If a yellow circle appears, then the monkey should pick up the yellow golf ball. A white circle indicates that the white golf ball should be picked up.

The monkey looks at the golf balls as she awaits the imperative stimulus. Activity occurs in the inferotemporal cortex to determine the object’s meaning. This likely helps the monkey recall that she will get a reward if she picks up the correct golf ball. Area AIP of the posterior parietal cortex also discharges as the object’s properties are identified. The golf balls are both small spheres, they have dimples, with the key difference that one is yellow and the other is white. The inferotemporal cortex projects to AIP where the objects’ meanings and properties are combined to form affordances. One affordance would be that the golf balls could be grasped and picked up. These are passed to PMvrab where they are used to prepare a plethora of potential grasps to both golf balls. All this activity occurs before the monkey is cued to pick up a specific golf ball.

A white imperative stimulus is displayed and the monkey begins to translate the stimulus into a response. This results in activity in the ventral PMdr and the pre-SMA. The parietofrontal PGm to ventral PMdr circuit is activated by response selection for conditional stimulus-response association tasks. The pre-SMA is also involved in complex stimulus-response translation. The connections from the prefrontal cortex to the pre-SMA allows the pre-SMA to act as a supramotor control center that triggers movements prepared in other motor areas when an action is required. Specifically, it receives the plethora of potential grasps from PMvrab and selects one that matches the response determined by the stimulus-response translation. This translation results in the monkey deciding to pick up the white golf ball with her right hand.

Now that the response has been selected, the motor areas begin to program the response. This movement preparation occurs in the cingulate motor areas and the premotor cortex. The premotor cortex uses parietofrontal circuits to transforms sensory information of the golf ball and the monkey’s body into the selected response. The VIP to PMvc circuit prepares the selected movement in a head-centered frame of reference. The PEip and PEc to PMdcd circuits and the MIP to PMdcvr circuit use somatosensory information to prepare the selected movement. The PMdcvr also uses visual information for movement preparation. These circuits will also be involved with online control of the executed movement.

Just before movement execution, activity occurs in SMA proper and M1. The parietofrontal circuit from the supplementary sensory area (PEci) to SMA proper prepares and executes the anticipatory postural adjustment that precedes the reaching movement. M1 also has a role in preparing and executing the anticipatory postural adjustment. To execute the selected response, activity occurs in the arm and hand region of M1 contralateral to the response. This activity results in a population vector that points in the direction of the movement. Almost all the motor areas connect with and contribute to the activity in M1. M1 is also influenced by connections from PE of the posterior parietal cortex that estimates the body’s location and by information from sensory receptive fields from the primary somatosensory cortex (SI). These connections are used for response programming as well as online control.

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This complex coordination of the motor areas allows the monkey to reach out and pick up the white golf ball. This example illustrates that even relatively simple movements require contributions from the entire motor network. This speculative coordination is one area for future research. The motor areas are typically investigated in isolation, so there is much to learn about the interactions that allow us to effortlessly execute even complex movements.

Acknowledgements

I wrote this document as part of my PhD comprehensive exams. I would like to thank my advisor, Professor Chua, for his support while I meandered into the field of neurophysiology. This document was completed for and reviewed by Professor Carpenter. His careful review and insightful comments led to many improvements in the document. Thank you, Professor Carpenter, for all your help. Finally, I would like to acknowledge the generous financial support from NSERC, UBC, and the School of Kinesiology.

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References

* of outstanding interest

Ape (nd). In Wikipedia. Retrieved November 23, 2011, from http://en.wikipedia.org/wiki/ApesBlumenfeld H (2010). Neuroanatomy through clinical cases (2nd ed). Sunderland, Massachusetts:

Sinauer Associates.Brodmann K (1909). Vergleichende Lokalisationslehre der Grosshirnrinde in ihren Prinzipien dargestellt

auf Grund des Zellenbaues. Leipzig, Germany: Johann Ambrosius Barth Verlag.Deecke L (1990). Electrophysiological correlates of movement initiation. Revue Neurologique, 146(10),

612-619.Dum RP & Strick PL (1991). The origin of corticospinal projections from the premotor areas in the frontal

lobe. The Journal of Neuroscience, 11(3), 667-689.Dum RP & Strick PL (1993). Cingulate motor areas. In: Neurobiology of cingulate cortex and limbic

thalamus (Vogt BA, Gabriel M, eds), pp 415-441. Boston: Birkhäuser.* A Great review on the cingulate motor areas.

Georgopoulos AP, Kalaska JF, Caminiti R, Massey JT (1996). On the relations between the direction of two-dimensional arm movements and cell discharge in primate motor cortex. Journal of Neuroscience, 2(11), 1527-1537.

Geyer S, Matelli M, Luppino G, Zilles K (2000). Functional neuroanatomy of the primate isocortical motor system. Anatomy and Embryology, 202(6), 443-474.* A great review of the motor areas of the frontal lobe but does not include the cingulate motor areas.

Halsband U & Passingham R (1982). The role of premotor and parietal cortex in the direction of action. Brain Research, 240(2), 368-372.

Holsapple JW & Strick PL (1989). Premotor areas on the medial wall of the hemisphere: Input from the ventrolateral thalamus. Society for Neuroscience Abstracts, 15, 282(114.5).

Jacobs JV, Lou JS, Kraakevik JA, Horak FB (2009). The supplementary motor area contributes to the timing of anticipatory postural adjustments during step initiation in participants with and without Parkinson’s disease. Neuroscience, 164(2), 877-885.

Kandel ER, Schwartz JH, Jessell TM (2000). Principles of neural science (4th ed). Norwalk, Connecticut: Appleton & Lance.

Keizer K & Kuypers HGJM (1989). Distribution of corticospinal neurons with collaterals to the lower brain stem reticular formation in monkeys (Macaca fascicularis). Experimental Brain Research, 74(2), 311-318.

Kolb B & Whishaw IQ (2003). Fundamentals of neurophysiology (5th ed). New York: Worth Publishers.Liu J, Morel A, Wannier T, Rouilier EM (2002). Origins of callosal projections to the supplementary motor

area (SMA): A direct comparison between pre-SMA and SMA-proper in macaque monkeys. Journal of Comparative Neurology, 443(1), 71-85.

Luppino G, Matelli M, Camarda R, Rizzolatti G (1994). Corticospinal projections from mesial frontal and cingulate areas in the monkey. NeuroReport, 5(18), 2545-2548.

Martin JH (2003). Neuroanatomy: Text and atlas (3rd ed). New York: McGraw-Hill.Massion J (1992). Movement, posture, and equilibrium: Interaction and coordination. Progress in

Neurobiology, 38(1), 35-56.Murray EA & Coulture JD (1981). Organization of corticospinal neurons in the monkey. The Journal of

Comparative Neurology, 195(2), 339-365.Nachev P, Kennard C, Husain M (2008). Functional role of the supplementary and pre-supplementary

motor areas. Nature Reviews Neuroscience, 9(11), 856-869.

25

Old world monkey (nd). In Wikipedia. Retrieved November 23, 2011, from http://en.wikipedia.org/wiki/Old_World_monkey

Olszewski J (1952). The thalamus of Macaca multatta. New York: Karger.Penfield W & Rasmussen T (1952). The cerebral cortex of man. New York: Macmillan.Picard N & Strick PL (1996). Motor areas of the medial wall: A review of their location and functional

activation. Cerebral Cortex, 6(3), 342-353.* A review of the cingulate motor areas and the supplementary motor areas that includes a metanalysis of fMRI studies on humans.

Rizzolatti G & Luppino G (2001). The cortical motor system. Neuron, 31(6), 889-901.* Focuses on the role of ventrorostral premotor cortex (AIP PMvrab, PF PMvrc) and pre-SMA.

Rizzolatti G, Luppino G, Matelli M (1998). The organization of the cortical motor system: New concepts. Electroencephalography and Clinical Neurophysiology, 106(4), 283-296.* Focuses on the parietofronal circuits between the posterior parietal cortex and motor areas in the frontal lobe.

Roland PE & Zilles K (1996). Function and structure of the motor cortices in humans. Current Opinion in Neurobiology, 6(6), 773-781.

Rothwell J (1994). Control of human voluntary movement (2nd ed). London: Chapman & Hall.Schlag J & Schlag-Rey M (1987). Evidence for a supplementary eye field. Journal of Neurophysiology,

57(1), 179-200.Stick PL, Dum RP, Picard N (1998). Motor areas of the medial wall of the hemisphere. In: Sensory

guidance of movement (Bock GR, Goode JA, eds), pp 64-80. Chichester, West Sussex, England: John Wiley & Sons.

Swinnen SP & Wenderoth N (2004). Two hands, one brain: Cognitive neuroscience of bimanual skill. Trends in Cognitive Sciences, 8(1), 18-25.

Talairach J & Tournoux P (1988). Co-Planar Stereotaxic Atlas of the Human Brain: 3-D Proportional System: An Approach to Cerebral Imaging, Thieme Medical Publishers, New York.

Tanji J (1996). New concepts of the supplementary motor area. Current Opinion in Neurobiology, 6(6), 782-787.

Tipper SP, Lortie C, Baylis GC (1992). Selective reaching: Evidence for action-centered attention. Journal of Experimental Psychology: Human Perception and Performance, 18(4), 891-905.

van der Knaap LJ & van der Ham IJ (2011). How does the corpus callosum mediate interhemispheric transfer? A review. Behavioural Brain Research, 223(1), 211-221.

van Donkelaar P, Stein JF, Passingham RE, Miall RC (1999). Neuronal activity in the primate motor thalamus during visually triggered and internally generated limb movements. Journal of Neurophysiology, 82(2), 934-945.

Vogt C & Vogt O (1919). Allgemeinere ergebnisse unserer hirnforschung. J Psychol Neurol (Leipzig), 25, 277-462.

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Appendix

Abbreviations

Motor areas of the frontal lobe

M1 Primary motor cortexSMAs Supplementary motor areas

SMA proper Supplementary motor area properPre-SMAPre-supplementary motor area

PM Premotor cortexPMdr Dorsorostral premotor cortex

SEF Supplementary eye field, also known as dorsal PMdrVentral PMdr Ventral dorsorostral premotor cortex

PMdc Dorsocaudal premotor cortexPMdcd Superior precentral dimple of the dorsocaudal premotor cortexPMdcvr Ventrorostral subarea of the dorsocaudal premotor cortex

PMvr Ventrorostral premotor cortexPMvrc Dorsal convexity of the ventrorostral premotor cortex, mirror neuronsPMvrab Arcuate bank of the ventrorostral premotor cortex

PMvc Ventrocaudal premotor cortexCMAs Cingulate motor areas

CMAd Dorsal cingulate motor areaCMAv Ventral cingulate motor areaCMAr Rostral cingulate motor area

Human motor areas

CCZ Caudal cingulate zoneRCZ Rostral cingulate zone

RCZa Anterior rostral cingulate zoneRCZp Posterior rostral cingulate zone

Macroanatomical landmarks

AC Anterior commissureAG Genu of the acruate sulcusAI Inferior arcuate sulcusAS Superior arcuate sulcusC Central sulcusCC Corpus callosumCG Cingulate gyrusCS Cingulate sulcusCSd Dorsal cingulate sulcusCSv Ventral cingulate sulcusIP Intraparietal sulcusIPD Inferior precentral dimple L Lateral fissureVCA line vertical line perpendicular to the midline of the anterior commissure

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Parietal cortex

SI Primary somatosensory cortexSII Secondary somatosensory cortexPPC Posterior parietal cortex

AIPLIPMIPPEPEcPEci Supplementary sensory areaPEipPFPFGPGPGmVIPV6A

Thalamus

MD Nucleus medialis dorsalisVAmc Nucleus ventralis anterior magnocellularisVApc Nucleus ventralis anterior pars parvocellularisVL Nucleus ventralis lateralisVLc Nucleus ventralis lateralis par caudalisVLo Nucleus ventralis lateralis pars oralisVPLo Nucleus ventralis posterolateralis pars oralisX Area X

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