OCD, Dopamine, and the Nucleus Acumbens
It is easy to mistakenly assume that behaviors seen in OCD (including grooming disorders) and Tourette syndrome are not goal directed—that they are senseless and meaningless. It may even feel senseless and meaningless to the person afflicted with symptoms. But there is a purpose behind the behavior—to reduce frustration and/or to release pent up SEEKING behavior, whether one is motivated to seek out attachments or resources.
"The Primate Basal Ganglia: Parallel and Integrative Networks" (2003), Suzanne N. Haber explains that "The basal ganglia [corpus striata complex] and frontal cortex operate together to execute goal directed behaviors." It is difficult to sum up this cooperative effort. Here, I will combine my words with some of Haber's concepts:
Amygdala-labeled emotions combine with dopamine-powered motivation to produce an impetus that the frontal cortex shapes via cognition to organize and plan strategy to shape motor output.
We can begin to better understand how dysfunctions occur when we better understand how normal behavior is engendered.
Regarding normal, primate behavior, including human behavior, Haber writes:
The components of the frontal cortex that mediate these behaviors are reflected in the organization, physiology, and connections between areas of frontal cortex and in their projections through basal ganglia circuits. This comprises a series of parallel pathways.
However, this model does not address how information flows between circuits thereby developing new learned behaviors (or actions) from a combination of inputs from emotional, cognitive, and motor cortical areas. Recent anatomical evidence from primates demonstrates that the neuro-networks within basal ganglia pathways are in a position to move information across functional circuits. Two networks are: the striato-nigral-striatal network and the thalamo-cortical-thalamic network. Within each of these sets of connected structures, there are both reciprocal connections linking up regions associated with similar functions and non-reciprocal connections linking up regions that are associated with different cortical basal ganglia circuits. Each component of information (from limbic to motor outcome) sends both feedback connection, and also a feedforward connection, allowing the transfer of information. Information is channeled from limbic, to cognitive, to motor circuits. Action decision-making processes are thus influenced by motivation and cognitive inputs, allowing the animal to respond appropriate to environmental cues.
In this section, we will discuss and clarify the structures and neurocircuitry involved in the parallel circuits Haber describes above.
On this page, I have borrowed several images of coronal sections of human brain from a Washington University in St. Louis (WUStL) Neuroscience Tutorial that is no longer internet accessible. Diana Weedman Molavi created the tutorial. The images originate from the collections of Joel Price, Harold Burton, and David Van Essen, Department of Anatomy and Neurobiology, WUStL. In these coronal sections, the myelin part of the tissue has been stained. So instead of its natural white appearance, in these particular images, the myelin appears black. The diagram to the right depicting coronal, horizontal, and saggital planes is also from the WUStL tutorial. Molavi writes: "Coronal sections are the easiest to visualize, because their orientation is just like looking face-on at another person. Up is up and down is down." The coronal images below correspond in orientation to the color-labeled illustration of the corpus striata complex used in OCD and the corpus striata complex (basal ganglia).
In Part 1 of MyBrainNotes.com, in The amygdala, stress, OCD, and PTSD, we discuss incentive salience with the help of authors Ramachandran and Oberman. The authors describe how the amygdalae create a salience landscape, a kind of directory that encodes the emotional significance of everything in an individual's environment. The emotion-packed interconnections between the amygdalae and the corpus striata complex figure prominently in the development of behavior including dysfunctional symptoms. In
"Neuropsychiatry of the Basal
Ganglia" (2002), H.A. Ring and J. Serra-Mestres explain the important anatomical links between structures governing emotive functions (the amygdala and hippocampus) and structures prompting subsequent motor functions (the corpus striata complex, also called the basal ganglia). To develop the material excerpted below, Ring and Serra-Mestres cite Andre Parent's and Malcolm B. Carpenter's book, Carpenter's Human Neuroanatomy.
The basal ganglia develop as part of the telencephalon, from the basal region of the mantle layer of the primitive telencephalic vesicle and the amygdala complex develops from the same tissue mass as the caudate nucleus. These findings emphasise that there are important links between parts of the brain that have classically been considered to be related to emotional functioning [amygdala] and parts of the brain that have in the past been considered to play a part largely in motor functions [basal ganglia/corpus striata].
Regarding the telencephalon, a forebrain structure, you may wish to review a previous discussion of brain development in Part 1 of MyBrainNotes.com called Neural tube brain organization. My take on the observations of Ring and Serra-Mestres is that both emotive and motor functions are essential components of our being. Without one or the other, we are neither human, primate, nor mammal.
In the image to the right from the Washington University in St. Louis Neuroscience Tutorial, you can see the globus pallidus labeled "GP externa" and "GP interna."
As we discuss in OCD and the corpus striata complex (basal ganglia), the corpus striata complex, which includes the globus pallidus, has been associated with obsessive and compulsive symptoms as well as movement disorders. In "Obsessive-Compulsive and other Behavioural Changes with Bilateral Basal Ganglia Lesions: A Neuropsychological, Magnetic Resonance Imaging and Positron Tomography Study" (1989), D. Laplane et al. report on eight patients who "shared the combination of bilateral basal ganglia lesions and a frontal lobe-like syndrome." The authors write: "Some patients showed stereotyped activities with compulsive and obsessive behaviour which were sometimes highly elaborate in pattern. … The lesions appeared to be confined to the lentiform nuclei [putamen and globus pallidus], particularly affecting the pallidum [globus pallidus], although there was generalized brain atrophy in 2 cases."
From the coronal orientation, the globus pallidus is situated more deeply within the brain than the nucleus accumbens. In the image below, the putamen and nucleus accumbens on the left partially block the view of the more deeply recessed globus pallidus. This image is from the Temple University School of Medicine's Department of Anatomy and Cell Biology website. Marvin Sodicoff created the site with adaptations from Rod Bain, Andrew Blum, and David Ni. I have added the labeling here. To see an unlabeled version and to practice identifying structures, click on the image.
Like the globus pallidus, the nucleus accumbens is a component of the larger corpus striata complex. Both the nucleus accumbens and the caudate-putamen project to the globus pallidus, also called the pallidum. In "Neuropsychiatry of the Basal Ganglia" (2002), Ring and Serra-Mestres clarify some anatomical issues. The first involves the term striatum. The caudate nucleus and putamen, both structures of the corpus striata complex, are together sometimes called the striatum. The nucleus accumbens is considered part of the ventral striatum; in other words the nucleus accumbens is in the lower part of the overall structure. The nucleus accumbens has both a core area and a shell area; these areas have different functions, neural projections, and morphologies (organization and appearance).
In the chapter on mammals in The Central Nervous System of Vertebrates (1998), Voogd, Nieuwenhuys, Van Dongen, and Ten Donkelaar write: "Because the nucleus accumbens receives massive projections from the hippocampal formation and the amygdala, both essential components of the limbic system, this cell mass has been hypothesized to constitute the functional interface between the limbic and the motor system
(Mogenson et al. 1980; Mogenson 1984; Hooks and Kalivas 1995)."
"The nucleus accumbens, which lies within the basal ganglia, may be a primary ganglion for the organization of action within the brain," writes Jay Schulkin in Effort: A Behavioral Neuroscience Perspective on the Will (2007). "Some time ago, Nauta (1961; Kelley, Domesick, & Nauta, 1982; Nauta & Domesick, 1982) suggested that the nucleus accumbens is an important link between the amygdala and motivation for the organization of action (Mogenson & Huang, 1973). Translation of motivational output from the amygdala to the behavioral outputs of the basal ganglia takes place via the connectivity to the nucleus accumbens (Kelley, 1999; Mogenson, Jones and Yim, 1980; Swanson, 2003)."
The one question I have regarding Schulkin's remarks above relates to his reference to the amygdala's "motivational output." I understand motivation to come primarily from the SEEKING system—the VTA to nucleus accumbens pathway (often called the mesolimbic dopamine pathway). One could say that the amygdalae ascribe salience and thereby shape and label dopamine-produced motivation or dopamine input to the nucleus accumbens. In discussing the SEEKING system, we have already discussed how neurons in the VTA produce dopamine that is released into the nucleus accumbens. So we will not revisit the SEEKING system here. For review, see Dopamine action, synthesis, and pathways and The Brain's SEEKING System. Once I am able to read all of Schulkin's book, I hope to clarify these issues.
The corpus striata complex manages neurosignaling from several distinct sources and serves as a sort of interchange between emotive, motivational, and motor neurosignaling.
Here, we are using the term motivational neurosignaling to mean the mesolimbic dopamine pathway. We are using the term motor neurosignaling to mean the nigrostriatal pathway. For review of the nigrostriatal pathway, you may want to take a look at Parkinson's Disease and dopamine.
Integrated, balanced emotive-motivational-motor neurosignaling eventually communicates to cortical regions that manage movement—the motor cortex. To oversimplify, senses/feelings prompt emotion that combines with motivation and, with cognitive/cortical influence, prompts movement/behavior. Needless to say, imbalances within the system can cause dysfunctional behavior or movement.
Emotive Function: Signals from the hippocampus and amygdala (often called limbic structures) flow into what is called the ventral striatum. As we discuss above, this area is the lower portion of the overall striatal structure and includes the nucleus accumbens. Incoming amygdala and hippocampus neurosignaling to the nucleus accumbens relate to the feelings and memories associated with what we see, hear, smell, taste, and touch in the world, including the feelings and memories associated with our interactions with other beings. In Part 1 of MyBrainNotes.com, in
Subcortical Brain Structures, Stress, Emotions, and Mental Illness, we discuss the memory forming role of hippocampus and the salience forming role of the amygdala, which in turn influence the hypothalamus and the autonomic nervous system. As Robert M. Sapolsky observes in Monkeyluv and Other Essays on Our lives as Animals (2005): "Sometimes, all you need to do is think a thought and you change the functioning of virtually every cell in your body."
Motivational Function: Again, here we are using the term motivational neurosignaling to mean the mesolimbic dopamine pathway and the SEEKING system as Jaak Panksepp defines it in Affective Neuroscience: The Foundations of Human and Animal Emotions (1998).
Motor function: The image to the right is credited to Donato DiMonte of the Parkinson's Institute and links to Cindy Lawler's succinct article regarding the epidemiology of Parkinson's Disease. The image depicts in vitro dopamine neurons (in other words these particular neurons are being maintained in an artificial environment). The upper portion of the overall striatal structure, called the dorsal striatum or caudate-putamen complex receives dopamine signaling from neurons similar to these in the nigrostriatal pathway. This pathway is directly associated with movement. Parkinson's Disease results when dopamine-producing neurons are depleted in the substantia nigra, where the nigrostriatal pathway originates (see Parkinson's Disease and dopamine).
In addition to basic movement, in "The role of nucleus accumbens dopamine in motivated behavior: a unifying interpretation with special reference to reward-seeking," Satoshi Ikemoto and Jaak Panksepp explain that "The nigro-striatal DA [dopamine] system appears to be a key structure involved in habit formation (stimulus-response learning)." In making this conclusion, Ikemoto and Panksepp cite, among others, N.M. White's "Mnemonic functions of the basal ganglia" (1997).
Before moving ahead to White's work, we will review some concepts related to memory. The New Oxford American Dictionary on my Apple MacBook defines the adjective mnemonic thus: "aiding or designed to aid the memory." There are different kinds of memory. Declarative memory relates to remembering facts and events. According to Wikipedia, "Procedural memory is our memory for how to do things. When needed, procedural memories are automatically retrieved and utilized for the execution of the step-by-step procedures involved in both cognitive and motor skills; from tying shoes to flying an airplane. This process occurs without the need for conscious control or attention. Procedural memory is a type of long-term memory and more specifically a type of implicit memory." And, "Implicit memory is a type of memory in which previous experiences aid in the performance of a task without conscious awareness of these previous experiences." Here, we are talking more about procedural and implicit memory. In White's "Mnemonic functions of the basal ganglia," the author writes:
A synthesis of older and recent work on mnemonic functions of the basal ganglia in rats, monkeys and humans emphasizes a reciprocal relationship of the caudate nucleus and putamen with the cerebral cortex, which mediates the memory of consistent relationships between stimuli and responses (sometimes called habits) that often involve relationships between the individual and its environment (egocentric memory). Evidence at several levels of analysis (including neuroplastic synaptic changes, activity of single neurons, and behavioral changes caused by lesions or neurochemical manipulations) implicate dopamine release from nigro-striatal neurons in the reinforcement, or strengthening, of neural representations in the basal ganglia.
In a 1984 article in Nature titled "Weaver mutation has differential effects on the dopamine-containing innervation of the limbic and nonlimbic striatum," Suzanne Roffler-Tarlov and Ann M. Graybiel establish a morphological distinction between corpus striata brain areas associated with emotive function and corpus striata brain areas associated with motor function. "The nucleus accumbens-olfactory tubercle region and abutting caudoputamen (together called the 'ventral' or 'limbic' striatum) are characteristically related to limbic parts of the forebrain, whereas the large remainder of the caudoputamen (the 'dorsal' or 'non-limbic' striatum) is most closely related to sensorimotor regions."
To sum up, the corpus striata complex is where sensory, emotive, motivational, motor, and cognitive neurosignaling converge. One small thing gone wrong in the corpus striata complex could possibly prompt the troubling OCD or Tourette syndrome symptoms where one is seemingly disconnected from one's will.
So how does the neocortex communicate with the subcortical corpus striata complex? In
"Frontal-Subcortical Circuits and Human Behavior" (1993), Jeffrey L. Cummings explains:
Five circuits are currently recognized: a motor circuit originating in the supplementary motor area, an oculomotor circuit with origins in the frontal eye fields, and three
circuits originating in prefrontal cortex (dorsolateral prefrontal cortex, lateral orbital cortex, and anterior cingulate cortex). The prototypic structure of all circuits is an origin in the frontal lobes, projection to striatal structures (caudate, putamen, and ventral striatum [includes nucleus accumbens]), connections from striatum to globus pallidus and substantia nigra,
projections from these two structures to specific thalamic nuclei, and a final link back to the frontal lobe. Within each of the circuits there are two pathways: (1) a
direct pathway linking the striatum and the globus pallidus interna/substantia nigra complex and (2) an indirect pathway projecting from striatum to globus pallidus
externa, then to subthalamic nucleus, and back to the globus pallidus interna/substantia nigra. Both direct and indirect circuits project to the thalamus. All circuits share
common structures—frontal lobe, striatum, globus pallidus, substantia nigra, and thalamus—and are contiguous but remain anatomically segregated throughout. Projections are progressively focused onto a smaller number of neurons as they pass from cortical to subcortical structures, but circuit segregation is maintained. There are open and closed aspects to the circuits; structures receive projections from noncircuit cortical areas, thalamus, or amygdaloid nuclei and project to regions outside the circuits. Structures projecting to or receiving projections from specific circuits are anatomically and functionally related. The circuits focus input on restricted cortical targets; several cortical regions project to the striatum, where the output is funneled through sequential circuit structures to limited frontal lobe areas.
To see a diagram of how the cortical-subcortical circuits are organized, including the direct pathway (labeled A - RELEASE) and the indirect pathway (labeled B - INHIBIT) mentioned above, link here to the
American Journal of Psychiatry. We will discuss the commentary provided with the graphic and photograph in the paragraphs below. Source: Images in Neuroscience, Carol A. Tamminga, M.D., Editor, Am J Psychiatry 158:1, January 2001.
Regarding the American Journal of Psychiatry graphic mentioned above, which I am unable to embed in this webpage, the GABA neurosignaling originates, at least in part, from the nucleus accumbens. As the graphic illustrates, GABA neurosignaling is of extreme importance in managing motor output—both in releasing motor activity and inhibiting motor activity. We will discuss this in greater detail below.
Because this subject is so complex, an excerpt from C.M.A. Pennartz et al., "Corticostriatal Interactions During Learning, Memory Processing, and Decision Making" (2009), is included here. Remember that pallidum is another term for globus pallidus.
Cortical projections to the striatum are topographically ordered in a series of parallel anatomical "loops" running from neocortex to the striatum, pallidum, thalamus, and back to neocortex. These parallel macrocircuits have been linked to different global functions: whereas a "limbic," ventromedial prefrontal [cortex]–ventral striatal loop has been delineated to mediate motivational and reward processing, other loops engage in sensorimotor or cognitive processing (Alexander et al., 1990 ; Graybiel et al., 1994 ; Voorn et al., 2004 ; Yin and Knowlton, 2006 ). Information processed along these pathways is under the modulatory control of dopamine released from fibers originating in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNpc). Given the parallel organization of corticostriatal circuits, the question arises how coherent behavior, requiring integration of sensorimotor, cognitive, and motivational information, is achieved.
In other words, coherent behavior is produced when these parallel circuits somehow share information. This brings us back to Suzanne N. Haber's article, "The Primate Basal Ganglia: Parallel and Integrative Networks" (2003), which we discuss above. Haber writes: "Recent anatomical evidence from primates demonstrates that the neuro-networks within basal ganglia pathways are in a position to move information across functional circuits."
The nucleus accumbens shell has a high density of dopamine (D1 and D3) receptors. Jaak Panksepp's observation in Affective Neuroscience bears repeating. He notes that the overall functions of the basal ganglia [corpus striata including nucleus accumbens] "are under the control of one major 'power switch'—ascending brain dopamine." Neurons in the ventral tegmental area (VTA) project, via the mesolimbic pathway, directly to the nucleus accumbens, where they release dopamine—one aspect of the ascending brain dopamine to which Panksepp refers. If you remember from material in Part 2 of MyBrainNotes.com, Panksepp concludes that the mesolimbic dopamine pathway and the mesocortical dopamine pathway are essential components of the SEEKING system, which directs our search for resources and solutions. (See Dopamine action, synthesis, and pathways and
The Brain's SEEKING System.)
To emphasize the importance of the nucleus accumbens as a link between the brain's emotive center (the hippocampi and amygdalae), motivational center (dopamine-producing neurons in the VTA in the midbrain), and motor center (dopamine-producing neurons in the substantia nigrae), I will quote more directly from the scientists who have studied the nucleus accumbens. In a 1983 The Journal of Neuroscience study titled "Neural Projections from Nucleus Accumbens to Globus Pallidus, Substantia Innominata, and Lateral Preoptic- Lateral Hypothalamic Area: An Anatomical and Electrophysiological Investigation in the Rat," G.J. Mogenson, L.W. Swanson, and M.Wu conclude: Since the nucleus accumbens receives substantial inputs from the hippocampal formation (Swanson and Dowan, 1977) and the amygdala (Krettek and Price, 1978; Newman and Winans, 1980), this evidence has led to the suggestion that it may serve as an important link between the limbic system on the one hand and somatomotor control systems on the other (Swanson and Cowan, 1975; Mogenson et al., 1980; Swanson and Mogenson, 1981).
The way I conceptualize motivated behavior in humans—being careful not to confuse motivation with will—is thus: the nucleus accumbens receives dopamine SEEKING signaling from neurons in the VTA along with emotionally-tagged VIGILANCE signaling from the amygdala and hippocampus. So what is the purpose of the nucleus accumbens? I propose that the nucleus accumbens may serve as an actuator, which the Princeton University WordNet defines as "a mechanism that puts something into automatic action." Such a function would ensure that, upon perceiving a threat, an animal could respond almost automatically with a bioprogramed sequence of behavior. Here, the term bioprogram refers to either 1) an innate neural firing pattern created via evolution that, like fixed-action patterns, involves specific movements and sequence, or 2) a learned pattern of neural activity that has been kindled to perform something like an innate bioprogram, or 3) a combination of innate and learned neural activity that have interdigitated over time through kindling. I conceptualize this third kind of bioprogram as being responsible for some post-traumatic stress symptoms. Think of the drills and routines soldiers learn in order to respond to threat. Once back at home in peaceful surroundings, those learned responses do not just vanish. And if a stimulus pops up unexpectedly—for example, a car backfiring—one might be forced to find a way to suppress behavior that, if acted out, would be inappropriate to one's environment. Having to do something to release surging motivation, one might engage in a displacement activity. In other words, symptoms would emerge. For a review, see Displacement, stereotypies, frustration, and perseveration—understanding ADHD, OCD, PTSD, and Tourette syndrome.
Even in times of threat, when an automated response helps ensure survival, the response cannot stay "on" forever. An animal or human would never get rest. This is where gamma-aminobutyric acid (GABA) comes in.
The Wikipedia image directly to the right (links to source) represents the chemical structure of gamma-aminobutyric acid (GABA). For details on GABA, see the Scholarpedia entry, which Eugene Roberts, who discovered GABA, curates. Click on the photograph of Roberts below right to read his biography.
In their abstract presented below from "Nucleus accumbens to globus pallidus GABA projection subserving ambulatory activity" (1980), D.L. Jones and G.J. Mogenson suggest that the nucleus accumbens releases gamma-aminobutyric acid (GABA) into the globus pallidus to attenuate motor activity. Thus, the GABA may be serving as a sort of "off" signal to the globus pallidus, which as we have discussed, is deeply recessed within the corpus striata complex and is an integral component in cortical-subcortical parallel circuits.
The Merck Manuals Online Medical Library explains that GABA is "the major inhibitory neurotransmitter in the brain. … After interaction with its receptors, GABA is actively pumped back into nerve terminals and metabolized." In the Jones and Mogenson study, when the authors blocked GABA with picrotoxin, motor activity increased. When they injected GABA into the system, motor activity decreased. So while dopamine input to the nucleus accumbens is certainly the "on" switch in the SEEKING system, it looks like GABA could be an "off" switch of sorts. When levels of either neurochemical are out of balance, during the integration of emotive, motivational, and motor neurosignaling, motor dysfunction could result. Jones and Mogenson write:
The present experiments investigated the hypothesis of a projection relating to the release of gamma-aminobutyric acid (GABA) from the nucleus accumbens to the globus pallidus subserving ambulatory activity in the rat. The GABA antagonist picrotoxin, microinjected into the globus pallidus, elicited dose-dependent increases in ambulatory activity. The administration of dopamine into the nucleus accumbens had a synergistic effect and further stimulated ambulatory activity. GABA injected into the ventral posterior globus pallidus significantly attenuated the ambulatory activity stimulated by injecting dopamine into the nucleus accumbens. These observations provide evidence of a GABAergic projection from the nucleus accumbens to the globus pallidus and implicate it in the initiation of ambulatory activity.
As a last note before leaving this subsection on the nucleus accumbens, I would like to note here that later in Part 3 of MyBrainnotes.com, we will discuss the successful use of deep-brain stimulation to the nucleus accumbens as a treatment for obsessions and compulsions.
Ann M. Graybiel and Scott L. Rauch, "Toward a Neurobiology of Obsessive-Compulsive Disorder" (2000), suggest that "parallel processing" may occur in the brain to allow emergence of OCD symptoms. They propose that while one circuit supports conscious information processing, another separate circuit might support automatic information processing. To avoid confusion with functional parallel cortical-subcortical circuits, however, I like to call this kind of dysfunction "autonomous processing." In other words, parallel circuits that normally share information across pathways to shape behavior, for some reason, begin to function autonomously.
This idea, I believe, is key to understanding many troublesome behavioral symptoms. For example, while one circuit focuses on cognition including problem solving and processing of whatever daily stimuli one encounters, another independent circuit might inappropriately prompt motor routines, especially routines generated from bioprograms that have, over evolutionary time, developed to discharge energy in the face of frustration or to maintain relationships (e.g., grooming). As we discuss in Part 2 of MyBrainNotes.com, when they occur out of context, such behaviors are called displacement activities and often include fixed-action patterns that can, under chronic stress, including isolation, turn into dangerous stereotypies. (See Fixed-action patterns and OCD and
Displacement, stereotypies, frustration, and perseveration—understanding ADHD, OCD, PTSD, and Tourette Syndrome.)
Although the science is high-level and difficult for me to interpret, I believe Charles R. Gerfen, in a 1984 article titled
"The Neostriatal Mosaic: Compartmentalization of Corticostriatal Input and Striatonigral Output Systems," elucidates the mechanism that, when functional and integrated, coordinates thinking-feeling behavior with motor behavior. When dysfunctional, however, the same system could result in autonomous processing, wherein emotional-cognitive signals are separately processed from motor signals in the corpus striatal complex. In other words, during such autonomous processing, you would be thinking about one thing and doing another thing.
The striatum (caudate-putamen) of the basal ganglia in the mammalian forebrain is a mosaic of two interdigitating, neurochemically distinct compartments. One type, the "patch" compartment, is identified by patches of dense opiate receptor binding and is enriched in enkephalin- and substance P-like immunoreactivity. The other compartment, the "matrix", has a high acetyl-cholinesterase activity and is shown here to have a dense plexus of fibres displaying somatostatin-like immunoreactivity. The present study demonstrates the two compartments have distinct connections, using a method that concurrently reveals striatal input, output and neurochemical systems in the rat.
Patches receive inputs from the prelimbic cortex (a medial frontal cortical area with direct "limbic" inputs from the amygdala and hippocampus); they also project to the substantia nigra pars compacta (the source of the nigrostriatal dopaminergic system).
Conversely, the matrix receives inputs from sensory and motor cortical areas; here it is shown to project to the substantia nigra pars reticulata (the source of the non-dopaminergic nigrothalamic and nigrotectal system). Also, an intrinsic striatal somatostatin-immunoreactive system is described that may provide a link between the two compartments. The striatal patch and matrix compartments thus appear to be functionally distinct and interactive parallel input-output processing channels.
In a short essay accompanying visuals in the 2009 American Journal of Psychiatry mentioned above, Ann M. Graybiel refers to striosomes and matrix components of the striatum. So what Graybiel calls striosomes in 2009, Gerfen called patches in 1984. Graybiel writes: "Already it is known that the matrix receives the striatal afferents most directly related to sensorimotor processing. In contrast, striosomes (including the entire ventral striatum) tend to receive inputs from neural structures affiliated with the limbic system, particularly the amygdala. Their segregated projections, intimately associated within the striatum, could subserve communication between these functionally distinct pathways.
The following paragraphs accompany the image to the right (links to source) in an award nomination called "Neurochemical Compartmentalizatin of the Striatum." I have added the bold emphasis.
Our brain can construct language, music and mathematics, but the same brain also lets us develop habits of thought and action. These semi-automatic routines free us to think and to attend to the world. Getting the right balance of what we do with conscious effort and what we do seemingly effortlessly by habit is part of the role of the basal ganglia, deep structures in the forebrain that interact with the neocortex above. The striatum, the main input structure of the basal ganglia, is responsible for much of what we call habit learning. Moreover, the striatum is centrally implicated in human neurologic and neuropsychiatric disorders. These range from problems that affect the motor system, as in Parkinson's disease, to problems that affect cognition and emotion and action control, as in obsessive-compulsive disorder, Tourette syndrome, depression and states of addiction. Imbalances in neurotransmitters in the striatum are now known to be important both for the normal functions of cortico-basal ganglia circuits and for the development of disordered functions in basal ganglia-based disorders.
This image [above right] illustrates a thin slice through the striatum of the human brain stained with a molecular stain that shows in white the distribution of one of the most important neurotransmitter systems in the basal ganglia, acetylcholine. Within the large white zones there are small gray zones of lower cholinergic staining. These are the striosomes (striatal bodies) that are thought to function in integrating emotional and cognitive signals with sensorimotor signals in the striatum. It is now thought that a balance between the striosomes and the extrastriosomal matrix is critically important in the balance between repeating the same action or choosing another action, and that disruption of this balance may contribute to dysfunction in basal-ganglia based neurologic and neuropsychiatric disorders. The jet black zone that cuts into the white-stained striatum is not the striatum, but the large bundle of fibers that interconnect the neocortex with the striatum and other sites. Striosomes were first identified in the human brain in 1978 by the Graybiel Laboratory at MIT.
In "The Role of Nucleus Accumbens Dopamine in Motivated Behavior: A Unifying Interpretation with Special Reference to Reward-Seeking," Satoshi Ikemoto and Jaak Panksepp emphasize that "all brain DA systems promote widespread sensory-motor arousal and competence within the brain." It is my contention that chronic stress can kindle changes in neurocircuitry, including excessive transmission of dopamine and that this can result in OCD, compulsive grooming, PTSD, and hypersensitivity that may look like ADHD symptoms. Or, looking at things another way, this kind of chronic stress might activate genetic vulnerabilities or exacerbate mild symptoms that otherwise would go undetected.
Ikemoto and Panksepp point out that aversive, stressful stimuli, including social isolation, appears to facilitate dopamine release in the nucleus accumbens. The authors note that experiments in rats involving foot shock and tail pinch indicate that both unconditioned and conditioned stimuli prompts this increased dopamine release. For nonscientists, Ikemoto and Panksepp offer the following primer on the differences between types of stimuli.
In the Pavlovian (or classical) conditioning procedure, biologically important stimuli are defined as unconditioned stimuli because they can trigger unconditioned responses, that are 'inborn' or 'species-typical' reflexes. Examples of unconditioned stimuli are food, water, and various noxious stimuli. When other comparatively neutral sensory stimuli precede the presentation of such unconditional stimuli, and this pairing is repeated, conditioning occurs. Conditioned responses that were not present prior to such pairings can be now observed when the previously neutral sensory stimuli are presented alone. The sensory stimuli are now referred to as conditioned stimuli.
In the next paragraphs, we will discuss several experiments more specifically to show how stress affects release of dopamine in the nucleus accumbens. If I interpret Ikemoto and Panksepp correctly, evolution is responsible for the increased dopamine release in these kinds of aversive-stimuli experiments. The increased dopamine enables animals within a natural habitat to aggressively seek safety. For humans in the modern world who encounter complex and conflict-laden stressful stimuli, however, such safety-seeking behaviors might not be so easy to put into action. I contend it is in situations of chronic stress that increased dopamine release, via possible actuator action of the nucleus accumbens, can prompt automatic behavioral responses—either motor, cognitive, or both—from a repertoire of atavistic or kindled bioprograms.
In anticipation of receiving cocaine, dopamine transmission in the nucleus accumbens of rats rises rapidly. In drug-addicted humans, scientists hypothesize that this surge of dopamine erodes their resolve to abstain. In other words, the dopamine surge activates learned behavior that is not easily controlled.
The caption for the image to the right (links to source) reads: "Rats trained to self-administer cocaine exhibited elevations in dopamine concentrations when they anticipated cocaine and again when they began to seek the drug." Arrows mark these increases in the illustration. Once a rat pressed the lever, anticipation and dopamine peaks, and with a cocaine infusion, dopamine plummets.
Perhaps excessive dopamine production due to stress may function in a similar way as the increased dopamine production seen in the anticipation
of cocaine in rat experiments. Perhaps excessive or repeated dopamine production somehow overwhelms inhibitory GABA activity, and in effect begins to automate and differentiate a learned behavior, without regard for whether the behavior is appropriate. In
Toward a Neurobiology of Obsessive-Compulsive Disorder," Graybiel eloquently explains the somatic marker hypothesis. "In what has come to be called the somatic marker hypothesis, Damasio and his colleagues suggest that exposure to particular stimuli or contexts reactivate somatic states (autonomic responses, as indicated in their experiments by galvanic skin responses) that, through experience, have become associated with the stimuli. They propose that in OCD, this reactivation of somatic markers in response to expected outcomes becomes excessive, driving the behavioral repetition."
So whereas incentive salience involves amygdala processing and labeling of stimuli, the somatic marker hypothesis relates to the whole-body (somatic) response to specific stimuli. Perhaps these two theories are more alike than different.
In a 1995 study of conditioned dopamine release designed in part to measure the effects of stress on dopamine release in the rat nucleus accumbens, N. Saulskaya and C.A. Marsden write: "The extracellular level of dopamine in the medial nucleus accumbens markedly increased for up to 40 min when rats were given mild footshock in the testing. When the rats were returned to the testing, but not given footshock (conditioned emotional response), there was an immediate and long-lasting (80 min) increase in extracellular dopamine." The authors conclude that their study's results "indicate that the acquisition of conditioned emotional response causes long-lasting changes in the mechanisms involved in the glutamatergic control of dopamine release in the nucleus accumbens."
Getting specific about dopamine fluctuations in certain regions of the nucleus accumbens,
Peter W. Kalivas and Patricia Duffy, in "Selective Activation of Dopamine Transmission in the Shell of the Nucleus Accumbens By Stress" (1995) write: "A microdialysis probe was placed in either the shell or core compartment of the nucleus accumbens and rats were exposed to mild footshock. Extracellular dopamine levels in the shell of the nucleus accumbens were elevated during the 20-min collection period immediately after discontinuing footshock. In contrast, the levels of dopamine remained unaltered in the core of the nucleus accumbens."
Differentiated processing takes place in cortical-subcortical loops. Within each loop there are neurochemical RELEASE mechanisms that prompt behavior and INHIBITORY mechanisms that restrict behavior. Symptoms might arise when the processing in these loops is not integrated or when the release and inhibitory mechanisms are out of balance.
In "A Psychological and Neuroanatomical Model of Obsessive-Compulsive Disorder" (2008), Huey et al. write: "The most accepted neuroanatomic model of OCD is based on the finding that there are separate cortico-basal ganglia-thalamic-cortical loops." We discuss these loops above in The brain's cortical-subcortical circuits.
Regarding cortico-basal ganglia-thalamic-cortical loops, Huey et al. discuss how the model explaining obsessions and compulsions has been refined "by specifying that overactivation of the direct pathway in the basal ganglia relative to the indirect pathway results in an orbitofrontal-subcortical hyperactivity." In the graphic provided in the 2009 American Journal of Psychiatry, the direct pathway is labeled "A-Release" and the indirect pathway is labeled "B-Inhibit." Note that this illustration implies that the direct and indirect pathways involve different dopamine receptors.
In Autonomous processing in the brain, above, we discuss how
emotive-cognitive neurosignaling and motor neurosignaling are processed—not only within differentiated circuits—but within different compartments within the corpus striata complex. Symptoms might arise when the processing in these compartments is not functionally integrated due to injury, disease or an overload of dopamine from either of two sources—the VTA or the substantia nigrae.
Regarding dopamine output to the striatum, in Dopamine action, synthesis, and pathways, we discuss how dopamine-producing neurons in the VTA project to the nucleus accumbens or the ventral striatum while dopamine-producing neurons in the substantia nigra project to the caudate-putamen or dorsal striatum. In "Learning and Memory Functions of the Basal Ganglia," M.G. Packard and B.J. Knowlton clarify further these projections in terms of patches (or "striosomes" including the entire ventral striatum / nucleus accumbens) and matrix compartments. They write: "Both striatal compartments receive dopaminergic input, although dopamine pathways originating in the ventral tegmental area and substantia nigra appear to primarily innervate the patch and matrix, respectively." In other words, SEEKING system, motivating dopamine produced in the VTA transmits directly to the nucleus accumbens (a patch/striosome area).
In "Obsessive-Compulsive and other Behavioural Changes with Bilateral Basal Ganglia Lesions: A Neuropsychological, Magnetic Resonance Imaging and Positron Tomography Study" (1989), D. Laplane et al. report: "The existence of distinct nonoverlapping circuits in the motor field or in the associative field can explain the fact that basal ganglia lesions may give rise to a clinical picture that is either purely motor, purely behavioural (as in some of our patients), or both." Also, Huey et al. point out that "patients with excessive nigrostriatal dopaminergic input (such as patients with Huntington's disease) have excessive motor output." We discuss Huntington's Disease in The corpus striata (basal ganglia) complex.
Excessive dopamine may kindle neural patterns. Such an overproduction of dopamine may occur when one is overly motivated to solve problems–that is, in cases of chronic stress including emotional stress.
Corticostriatal Interactions during Learning, Memory Processing, and Decision Making, Pennartz et al. write, "Components of the neocortical-basal ganglia loops are essential for learned actions to become habitual, and abnormal activity within these loops is implicated in a range of clinical disorders related to action compulsion (as in obsessive-compulsive spectrum disorders and drug addiction) and action disability (as in Parkinson's disease and Huntington's disease) (Graybiel, 2008)." The authors go on to describe highly technical experiments using rats as subjects. The results of these experiments "indicate that habit formation and modification do not involve turning on and off a striatal 'habit system,' but rather a dynamic repatterning of neural activity (Barnes et al., 2005)."
As we discuss throughout Part 2 of MyBrainNotes.com regarding ancestral brain systems (See Emotions are Hard-Wired in the Brain: Introduction to Ancestral Brain Systems), emotive neurosignaling is often paired with action-oriented motor behavior although the two are processed in separate compartments of the corpus striata complex. In functional systems, the two modes of behavior are coordinated. As Panksepp explains, emotional systems have "intrinsic response patterning mechanisms, and one of the main functions of higher brain evolution has been to provide ever-greater flexible control over such mechanisms." So what defeats neocortical control, allowing for obsessions and compulsions? I contend there are several variables that might disrupt the integration of emotive-cognitive neurosignaling with motor neurosignaling within the corpus striata complex, resulting in symptoms. We discuss these variables in OCD risk factors. In summary, these risks can be genetic, epigenetic, injury-related, viral induced, or involve chronic stress that kindles vulnerable neurocircuits.
Regarding kindling, in the section titled Dopamine-driven bioprograms in the brain, we focused on how chronic stress increases dopamine within the nucleus accumbens, and how such an overload of dopamine might eventually overwhelm the inhibitory action of GABA, turning the nucleus accumbens into a sort of actuator for prompting kindled neural patterns. Although I have included the following information previously, it bears repeating: "The nucleus accumbens, which lies within the basal ganglia, may be a primary ganglion for the organization of action within the brain," writes Jay Schulkin in Effort: A Behavioral Neuroscience Perspective on the Will (2007). "Some time ago, Nauta (1961; Kelley, Domesick, & Nauta, 1982; Nauta & Domesick, 1982) suggested that the nucleus accumbens is an important link between the amygdala and motivation for the organization of action (Mogenson & Huang, 1973). Translation of motivational output from the amygdala to the behavioral outputs of the basal ganglia takes place via the connectivity to the nucleus accumbens (Kelley, 1999; Mogenson, Jones and Yim, 1980; Swanson, 2003)."
Here again is N.M. White's observation: "Evidence at several levels of analysis (including neuroplastic synaptic changes, activity of single neurons, and behavioral changes caused by lesions or neurochemical manipulations) implicate dopamine release from nigro-striatal neurons in the reinforcement, or strengthening, of neural representations in the basal ganglia." So while dopamine from the VTA may prompt the nucleus accumbens to initiate a neural pattern, perhaps it is the dopamine from the substantia nigrae that kindles that neural pattern. To be sure, dopamine is involved.
I contend that dopamine promotes the kindling process which can in turn 1) create hard-wired, hypersensitive neural networks or bioprograms or 2) that can sort of hijack and build on atavistic fixed-action patterns.
Our physical existence is organized around pattern generation. Is it any wonder that dysfunctions in our brains might prompt patterned behavior inappropriate to our complex human situations?
Packard and Knowlton write: "With regards to learning and memory functions, one interesting recent hypothesis is that fronto-cortical-striatal loops are used by the basal ganglia to essentially train the cortex to produce learned motor responses in the presence of a particular pattern of sensory information (Wise et al. 1996). However, it is important to note that, although basal ganglia output is clearly looped via the globus pallidus and thalamus back to specific cortical sites, pallidal and nigral outputs also directly project to downstream brain-stem structures that allow for rapid access to spinal control of motor responses."
In trying to understand any kind of behavior, it is important to recognize the importance of pattern generators in the brain. An area of the brain stem known as a central pattern generator, for example, controls the complexities of our breathing. Regarding central pattern generators, Neil Shubin explains in Your Inner Fish: A Journey Into the 3.5-Billion-Year History of the Human Body (2009) that these kinds of mechanisms "produce rhythmic patterns of nerve and, consequently, muscle activation." He adds: "A number of such generators in our brain and spinal cord control other rhythmic behaviors, such as swallowing and walking."
Toward a Neurobiology of Obsessive-Compulsive Disorder," Graybiel writes: "One hypothesis emerging from these findings is that the basal ganglia may influence both motor pattern generators in the brainstem and spinal cord and “cognitive pattern generators” in the cerebral cortex. By this view, the loops running from the neocortex to the basal ganglia and then to the thalamus and back to the neocortex may help to establish cognitive habits, just as they may influence the development of motor habits (Graybiel, 1997). If so, the cortico-basal ganglia loop dysfunction in OCD could reflect both sides of basal ganglia function, motor and cognitive, to bring about repetitive actions (compulsions) and repetitive thoughts (obsessions)."
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