One of the fundamental working hypotheses of modern neuroscience is that the functioning of the brain permits and shapes the expression of the mind. Cognitive, perceptual, affective, and behavioral capacities and limits are determined by neural structures and the dynamic flow of information within them. The shifting contents of momentary experience are the product of precisely coordinated, ever-changing combinations of electrical activity within richly connected neural networks. Put another way, neural states encode mental experiences. These complex neurobiological processes are scaffolded by evolution via inherited factors, animated by environmental inputs, and chiseled by experience and learning. The system learns about itself and the workings of its environment through continuous prediction and feedback, self-generated actions and environmental inputs shape this dynamic neural circuitry. Brain-behavior relationships are complex but patterned: specific neural activities support specific mental states and localized brain dysfunction leads to focal neurobehavioral changes. This schematic framework relating brain and mind is embedded in the clinical fields of behavioral neurology and neuropsychiatry and serves as this chapter’s main axiom.
There are many schemas for how to understand the brain’s role in supporting mental functioning. Highlighted below are several working hypotheses about brain organization that help to frame and add explanatory depth to the discussion of focal neurobehavioral syndromes. These ideas are introduced to stimulate the creative clinician to connect bedside observations not only to neuroanatomy, but to more foundational principles of cognitive neuroscience. Clinicians have a front-line opportunity to test, challenge, and improve these models to better understand and care for our patients. If past is prologue, clinician-driven ideas about brain-behavior relationships also promise to change our basic understanding of human cognition, affect, and behavior.
The brain is composed of specialized neurocomputational units whose activity is determined by local neurobiological factors
The brain is a collection of modular, often anatomically localized, units each designed to perform a specialized type of neural computation. The coordinated activity of these neural transformations form networks that encode the complex neural representations supporting cognition, affect, and behavior. Individual units receive information, perform a specific transformation, and share the result with other units. The dynamic integration of information flowing across multiple neurocomputational units supports the incredible diversity of cognitive functions. The particular transform performed by an individual unit is determined primarily by the neurobiological properties of its local brain tissue (e.g., cytoarchitecture, cell types, etc.).1 A given unit is capable of receiving, transforming, and transmitting information from many different units/areas2 via white matter pathways. It can contribute to a wide variety of functions depending on its connections with other units, enhancing efficiency. In contrast, a single function may be accomplished by different combinations of parts/units, which provides redundancy in case of injury. The redundancy idea—that there are multiple ways to perform a task—makes it difficult to precisely pinpoint the disrupted units/parts for any observed change in behavior. The flexible employment of these units and their networks supports mental functioning.
The pattern and strength of connectivity between units varies, and is determined by structural factors (e.g., presence/density of white matter tracts, synaptic density, etc.) and functional considerations (e.g., dynamic engagement of intact pathways in real time). Multiple units sharing and transforming information is referred to as a neural “network.” Networks generate complex combinations of transformed information and support higher-order representations. Dynamic shifts in network activity support the diversity of neural processes that underlie cognition, affect, and behavior. These shifts are mediated by neurochemical and neurophysiological processes.
This organizational structure supports the capacity for single units (e.g., nodes) to participate in multiple different networks, enhancing the system’s efficiency. Color combinations provide a simple illustration of this efficiency. Weighted combinations of red, yellow, and blue (i.e., a 3-unit color network, each a single computational unit) can represent a nearly infinite set of colors, which is much more efficient than representing each possible color combination as its own unique entity. Spatial coordinates are similar: an infinite possibility of three-dimensional locations can be represented as weighted values along just three axes (e.g., a 3-unit spatial network). Combining the information within these two 3-unit networks—color and space—allows any color to associate with any location, producing a nearly infinite set of color-location combinations. Because the information from each network is represented simultaneously (e.g., in parallel), an entirely new, synergistic entity is created (“color-location”), much like “green” is not just yellow-blue. For non-synergistic color-location combinations (e.g., a specific color at a specific location), a single 3-unit network can be utilized in series, with a fourth node serving to hold/store the first representation (e.g., color) while the second is being processed (e.g., location).
These same phenomena occur on larger scales in the brain and offer a conceptual mechanism by which complex states are generated via dynamic combinations of individual computational units participating in networks. Representations generated by one network (e.g., visual) can be combined with other networks (e.g., language) to form more complex representations (e.g., letters), which in turn can be combined yet again (e.g., written words). The iterative nature of the system allows a single neurocomputational unit to participate in many networks and support a wide array of mental functions.
Specific cognitive, affective, and behavioral expressions do not emerge from activity contained within single, specific, anatomically localized regions (e.g., as posited by phrenology). Precise, dynamic combinations of multiple, often anatomically disparate, interacting neurocomputational units are responsible for their genesis. Some suggest that these interactions have synergistic or emergent properties that cannot be explained by studying the individual components in isolation.
Sensory inputs are the building blocks of perception, which is also shaped by genetics, prior experience, and context
The brain uses sensory inputs to create perceptual content. Perturbations in the physical properties of the world—both the external environment and internal bodily states—are detected by biological receptors and translated into codes stored in the activity of neurons. These environmentally proximate codes/units are the raw data from which the brain models the world. These basic codes are combined, filtered, and layered together to form higher-order assemblies that constitute the architecture of perception. The assembly process is designed to detect and highlight potential salience in the data and is shaped by evolution/genetics (e.g., hard-wired recognition of salient patterns), prior experience (e.g., associative learning of stimuli with salient outcomes), and the behavioral context. Once these perceptual models have been sufficiently grounded and informed by incoming sensory information, they can be dynamically untethered from sensory systems and repurposed for other cognitive operations such as imagination.3
Experience Is Animated within the Brain’s Perceptual Machinery
The brain relies on its perceptual machinery to ground and express its knowledge and models of the world. These perceptual processes can be guided and manipulated by many different types of stimuli, and the nature of this influence encodes meaningful distinctions between different aspects of mentation. Perception that is constructed directly from incoming sensory streams (e.g., vision, audition), for example, supports the perception of the external world; guidance by internally generated motor plans supports perception of prepared/imagined actions; guidance by internally generated cognitive processes supports perception of thoughts, imagined scenes, or abstractions. The functioning of these different perceptual modes is shaped by one’s genetic milieu, prior experiences, and the behavioral context, all of which serve to filter and inform one’s perceptual expectations (see below). Perception and action are intimately connected; action—in its most broad sense—is that in the body or mind which disturbs perception.
The Brain Detects Patterns in Multiple Levels of Perception and Generates Predictive Models
Continuous streams of incoming sensory information are not random; they contain patterns in their sensory features and temporal flow. The brain discerns and stores these featural-temporal patterns and uses them as predictions about the state of the world. These serve to “fill in the gaps” later when incoming information is incomplete, ambiguous, or noisy. Repeated exposure to specific sensory inputs that are reliably followed by other sensory changes in close temporal proximity underlies rudimentary predictive models of causality. Stable sensory features across multiple temporal contexts support basic models of form, defined broadly as the configuration of objects and other perceptual phenomena. The information from these basic models is combined and integrated into higher-order featural-temporal assemblies, whose patterns are themselves detected, stored, and used to generate new predictions about the world. This process is iterative and expansive with each round of successive integration. The higher-level predictions feed back upon lower levels, too, creating both top-down and bottom-up influences. In totality, these dynamic multilayered prediction models constitute the large-scale, personal schematic frameworks about how the world works. They are the substrate for expectation, originally built into the neural structures from basic sensory building blocks. Cognitive processes combine and repurpose these working models of causality, form, and expectation to ground imaginations or abstract reasoning in conceptual schemas.
The brain constantly generates and updates predictive models about the self, the world, and their salient interactions. Data that are not consistent with expectations (i.e., a prediction error) are used to update the model’s predictive settings. The ability to represent self (as distinct from nonself) and generate schemas about the world—and one’s causal relationship to it—are supported by predictive processing. The predictions themselves are often used by the brain to guide decision making, judgements, and behavior, which highlights the importance of the model’s accuracy and tuning. The ability to adapt one’s predictive schemas based on new information varies across individuals, as does the ability to filter out data that do not fit the prediction.
The Brain’s Ability to Adapt to Its Environment Depends on the Behavioral Function and Developmental Stage
The brain’s different individual structures vary in their ability to adapt to changes in the environment. Many systems—often located in the brainstem—are inflexible and optimized to efficiently perform a stereotyped response whenever they become activated. These processes are often inborn and automatic, much like a motor reflex (although often more complex). Other parts of the central nervous system—particularly the cerebral cortex—are heavily dependent on environmental inputs (i.e., experience) to shape their particular expression. While certain areas are evolutionarily primed to support a particular function (e.g., inferior frontal gyrus [IFG] for speech output), their precise tuning and behavioral expressions are individualized based on one’s experience (e.g., individual accents). The ability of neural tissue to adapt and reorganize itself (i.e., neuroplasticity) based on changing environmental inputs varies over the course of the lifespan. There are often critical periods of high plasticity during development, when experiences have a marked impact on neural organization and subsequent behavioral expression.
Sensory and Motor Processes Represent Two Sides of the Same Coin
Just as sensory information shapes action, actions have sensory consequences. A simple movement of the arm leads to changes in the external environment which can be detected by visual and/or somatosensory systems, and also causes changes in the internal environment which can be detected by proprioceptive and visceromotor mechanisms. Specific actions lead to specific sensory consequences, and these relationships are stored as integrated sensorimotor associations that serve as predictive models coupling actions with perceptions. The codes can be accessed in a bidirectional manner: merely perceiving specific actions performed by others activates the motor programs required to perform the action. This is the so-called “mirror neuron” system.4 This perception-action coupling is what is known as the common coding hypothesis: the idea that action and perception are tightly linked5 as two aspects of an overlapping process. The brain utilizes these common codes to plan actions based on the anticipated sensory consequences, and specific actions can be induced by perceptual inputs.
Action-perception coupling may have broad implications for understanding behavior and cognition when considered as a general principle that extends beyond simple skeletal movements and their tactile/proprioceptive consequences. Perceiving the social behavior and/or affection of others may activate similar internal self-representations (“affect sharing”),6,7 including visceromotor programs; specific cognitive “actions” can specifically alter the contents of one’s working memory stores or imagination for problem solving. The tight linkages between different forms of action and perception offer a potential mechanism for many aspects of behavior, including reduced empathy in autism.8
The Brain Is Composed of Several Large-Scale, Often Anti-Correlated, Networks that Support Different Processing “Modes”
The brain tends to utilize several large-scale (e.g., multiple, anatomically distant) networks that support specialized “modes” of cognition. A mode is a wide set of preferential engagements with attentional, cognitive, perceptual, emotional, and action-generating machinery that represent restricted ways of interacting with and manipulating the mental and physical environment. These processing modes support different functions, such as tasks that require goal-driven externally directed attention or those supporting focus upon one’s own internal mentalizations such as thought, imagination, recollection of prior memories, and others. The coordinated activity of these large-scale networks amplifies and dampens certain cognitive processes by facilitating different connectivity patterns between brain regions, producing a broad set of specialized and highly efficient interactions at the expense of others. The activity of one mode is often most effective when the activity in others is suppressed. The brain switches between modes depending on the needs of the individual, and certain functions necessitate multiple modes acting in concert.
Many Aspects of Neural Processing Occur Outside of Conscious Experience
Most of the brain’s processing is hidden from consciousness. This is true for perception, action, cognition, and behavior. Incoming sensory stimuli, for example, are highly processed before entering one’s conscious awareness and are often perceived as a cohesive whole without perception of its deconstructed low-level components. In terms of action, a high-order behavioral plan may be conceived and directed within one’s consciousness while the complex series of smaller microactions needed to enact the plan within motor-effector systems are performed outside one’s conscious control. Conscious (“explicit”) processing is usually reserved for the highest-order functions, with most of the brain devoted to activity outside of consciousness (“implicit” processing). The reach of consciousness into lower levels may vary based on the ongoing needs of the individual.
Patients with deficient explicit processing may lack insight and have difficulty relaying the nature of their symptoms; their declared beliefs may not align with their outward behaviors. Excessive explicit processing can be disruptive, bringing into consciousness functions or stimuli that are best handled implicitly.
A Brief Note on the Problem of Consciousness
Despite the seemingly irreducible quality of one’s own conscious awareness, direct observation and detection of other minds poses philosophical difficulties. Generally accepted methods of scientific inquiry measure phenomena that are accessible via a third-person perspective (e.g., physical world and its forces); the qualitative experience of consciousness is accessible only through first-person introspection. As such, mental states may only be inferred based on indirect measurements such as behavior and neurophysiological data. The tension of not being able to directly measure the object of highest interest—the mind—permeates cognitive neuroscience and its clinical companions, behavioral neurology and neuropsychiatry. Discussions of “mental” states are often avoided and are replaced by alternative terms such as “representation,” which refers to neurologic states whose biological composition/readouts correlate with reported first-person experiences of specific mental states. This chapter continues in the tradition of avoiding this central philosophical mind-body problem, preferring to use “representation” when referring to psychological states.
Philosophical conceptions aside, consciousness is often divided into different components, including arousal/wakefulness and awareness. Deficits in these systems are termed disorders of consciousness. Reduced arousal, which is described by the amount of stimulation needed to generate the appearance of wakefulness, can manifest as total unresponsiveness, known as coma, or reduced responsiveness, known as stupor or lethargy. Excessive arousal may be seen in states of mania or agitation. Awareness is the conscious perception of specific mental representations or processes (e.g., the contents of consciousness). Many cognitive, perceptual, affective, and behavioral processes normally unfold outside of one’s awareness, often in a graded manner, suggesting a physiologic role for regulating the content of one’s consciousness awareness. When the control of awareness is dysfunctional, it can produce symptoms or reduced insight, known as anosognosia, which can be global or focal, but often involve the nondominant hemisphere.
The rest of the chapter is focused on the specific anatomical networks and organizational structures whose disruption or injury leads to common neurobehavioral syndromes. The basic principles reviewed provide a schematic context for the remainder of the chapter and serve as a foundation for the discussions about brain-behavior relationships. For a more detailed presentation of the functional neuroanatomy of cognitive processing, please see the authors’ related work, Chapter 3, of this volume.
The brain’s models about the world are informed by and grounded in its connections with the physical environment, both external and internal/body. Sensory-perceptual systems receive input from the external world in the form of light, pressure waves, chemical compounds, tactile displacement, and others, representing the basic inputs for vision, sound, olfaction and taste, and touch, respectively. They receive inputs from the body that relay information about the body’s physical position in space, markers of tissue damage, and internal homeostatic functions (e.g., chemical states of the body, autonomic states, visceral organ sensation, metabolic demands, etc.), and others. These basic sensory inputs are the building blocks of perception that underlie many aspects of cognition and behavior.
Disruptions of these distal sensory systems can produce neurologic symptoms affecting aspects of cognition and behavior. Some are intuitive: hearing loss due to inner ear damage can affect speech perception and blindness caused by ocular problems can affect reading, writing, and drawing. Others are less obvious: peripheral sensory damage can produce “release” hallucinations of simple or well-formed unimodal hallucinations after acquired visual or hearing loss (NB: Charles Bonnet syndrome refers to well-formed visual hallucinations after acquired vision loss), or the “phantom limb” phenomenon after limb amputations and its accompanying loss of body state inputs. Similar symptoms may also affect the olfactory system, a condition known as phantosmia.9 Despite the reduced peripheral input, central perceptual representations remain intact and can become activated in the absence of sensory inputs. Activation of higher-order perceptual representations without direct stimulation from sensory inputs supports normal cognitive functions, such as imagination and language. When dysregulated, however, it can lead to experiences of excessive or inappropriate mentalization, such as hallucinations.
A sudden change in peripheral sensory functioning leads to prediction errors about the sensory consequences of one’s actions. This can result in a retuning of the action-perception machinery and consequent changes in behavior. Hearing loss, for example, may cause a compensatory increase in the volume of one’s speaking voice; a reduction in autonomic inputs from the body lead to compensatory tachycardia upon standing as is reported in some cases of the postural orthostatic tachycardia syndrome (POTS). Altered sensory inputs can also lead to imprecise afferent predictions, leading to incorrect central activations and misperceptions and experience of illusions, especially in patients with cognitive impairment. These kinds of changes are sometimes misdiagnosed as occurring secondary to central nervous system damage or primary psychiatric conditions. Screening for peripheral sensory changes is an important component of the cognitive and behavioral evaluation.
Sensory perception—the awareness of incoming sensory information—is a higher-order process that depends on the cerebral cortex. The primary sensory cortices support basic perceptual processing of unimodal sensory inputs. Damage to these primary sensory cortices can produce clinical syndromes that illustrate the distinction between sensation and perception. Bilateral damage to the primary visual cortex, for example, can produce “blindsight,” where patients qualitatively experience total blindness yet respond to some visual stimuli with better-than-chance success rates. Despite their insistence on being blind, affected individuals duck when an object is thrown toward them, actively avoid tripping on obstacles placed in their line of gait, and make accurate guesses about information presented in their affected visual fields. They are unable to provide an account of their vision and are often bewildered by their unexpectedly effectual behaviors. Similar syndromes are reported with other sensory modalities, including cortical deafness after bilateral superior temporal damage, and cortical somatosensory loss after lesions to the post-central gyrus. Blindsight illustrates the important role of the cortex in explicit perceptual processing and forces the realization that conscious perception—despite its subjective quality as offering an immediate, foundational, unfiltered window onto the world—is an “active” process that requires specialized cortical neural machinery to compute.
Sensory perception is a multilayered process whereby successive rounds of neural processing encode increasingly complex perceptual representations. Informational flow through these systems often occurs via distinct pathways that support different types of perceptual processing. The visual system, for example, has dedicated areas for the processing of color, depth, motion, and object forms; the auditory system has specialized pathways representing sound as language (e.g., phonology). Other sensory modalities have a similar organization with specialized unimodal features. Damage to these higher-order, “secondary” sensory processing streams can produce modality-specific focal perceptual symptoms. Damage to phonological processing areas in the bilateral posterior superior temporal lobe, for example, may cause “pure word deafness,” whereby one cannot comprehend the meaning of spoken words but can read and understand the same words without difficulty. Disruption of the motion-sensitive areas in the visual cortex, area MT (or V5), produces symptoms of akinetopsia (“motion blindness”).
Adjacent to the secondary sensory cortices are multimodal sensory areas, where information from multiple sensory modalities is integrated into high-order perceptual representations. These areas support diverse functions such as the ability to perceive the world as a multidimensional, multimodal scene (like in a movie) or conceptual schemas of objects, abstract concepts, and other types of semantic knowledge. These multimodal areas are richly connected with other neurologic systems (e.g., “hubs”), which support their role in cognition and behavior.
The cognitive systems are traditionally organized into domains of mental processing (e.g., attention, executive functioning, visuospatial skills, language, praxis, calculations, etc.). This scheme did not originate from an understanding of functional neuroanatomy but rather neuropsychological models of cognition. Mapping these psychologically organized functions onto neuroanatomical networks is complex. Different cognitive functions may recruit similar or overlapping networks, and similar cognitive functions may be mediated by different neural pathways. For example, both recalling past memories and imaging future scenarios are different cognitive functions that utilize similar functional neuroanatomy. Alternatively, copying a four-sided figure with equal-length lines and right angles can be achieved by simply seeing and reproducing the lines on the page without knowledge of its identity as a square; alternatively, one can recognize the figure as a square and call upon one’s concept of squares to reproduce the figure. The same cognitive function—copying a figure—is potentially accomplished through multiple pathways. “Focal” neurobehavioral syndromes do not necessarily imply a specific focal anatomical lesion, but often point to disruption somewhere within a complex neural network. “Localization” of function is often characterized in terms of network failure, even when there is a solitary focal lesion. Despite the complex alignment of psychology and neuroanatomy, general principles of cognitive localization nevertheless emerge. The chapter continues the convention of organizing the cognitive system by its neuropsychological domains.
It is important to keep in mind that neuropsychological functions are hierarchical and interdependent, as the successful expression of some mental faculties requires that other functions to be at least partially intact. An obvious example is that of arousal (i.e., wakefulness): a stuporous patient will perform poorly on cognitive tests across multiple domains (e.g., attention, language, memory), even if the domain-specific neuroanatomical systems underlying these functions are themselves not damaged. Disturbances in this arousal-wakefulness system can yield a false sense of localization when not considered as part of a hierarchical organization. This is also true for motivation, as an unmotivated or unengaged participant is apt to perform poorly on many cognitive tests, which can lead to incorrect conclusions as to the localization of disrupted networks. Attention, concentration, executive functions, language, and visuospatial skills, as well as elemental neurologic functions (e.g., motor, coordination, sensation) all influence a patient’s performance on testing—including on measures designed to isolate specific cognitive domains—and it is important to understand and consider the cognitive operations required to carry out each test to avoid drawing improper conclusions. It is the interdependency of these functions that makes localization so challenging … and rewarding.
The neurobiological substrates supporting language processing provide an elegant demonstration of structure-function relationships in behavioral neurology and neuropsychiatry. The chapter’s early emphasis on language disorders serves to highlight general principles that apply to other neural/cognitive systems. Below, a detailed discussion of the language system is followed by briefer descriptions of the other systems.
CHARACTERIZING DEFICITS AFFECTING THE LANGUAGE SYSTEM
The faculty of communication through language is remarkable. The presence of sounds in the air, scribbles on a page, raised dots on a paper, and others, efficiently transforms the state of our brain into one of shared representations with their author, albeit filtered through our social lenses. These sensory symbols co-opt our perceptual machinery and effortlessly generate and proliferate concepts and mental imagery that spread through the nervous system to impact behavior. Human brains are uniquely designed to efficiently transmit their brain states—and receive those of others—via the coded mechanisms of language. Our facility in using these codes separates us from other animals; it allows us to communicate across time and space about specific entities that are not within our immediate perceptual environment. Language enables us to have connected brains, to be less alone, to become less isolated.
Communicating with language fundamentally requires one decode sensory inputs into language symbols, link these symbols with properly formed concepts, and produce sensory language symbols that others can interpret. These faculties comprise the core “language” system. In the real world, however, language is employed for social purposes: to share desires, concerns, and ideas, acquire knowledge from others’ experiences, and develop schemas about other minds. These real-life language functions extend far beyond that of symbol-semantic relationships and depend on cognitive, motivational, and perceptual skills. Paralinguistic expressions such as affective prosody (e.g., the emotional “tones” of speech), metaphor, sarcasm, body language, and conversational turn-taking connect language skills with complex limbic, social, and perceptual networks. Storytelling engages executive control and memory systems. Listening and reading requires attention and concentration. Lesions anywhere along this extended multidomain network can manifest as difficulty communicating with language, even when the fundamental language operations are spared.
Comprehending language depends on perceiving sensory phenomena as symbolically representative of semantic concepts. Each language’s sensory code is composed of a small set of learned elements (known as “features”) that serve as building blocks for higher-order linguistic structures. Specific combinations of these features make up the sensory word forms that connect to specific semantic concepts. Concepts that are paired with specific word forms are referred to as lexical concepts, or lemma (colloquially, “words”). Communicating requires that speakers and listeners have a common set of word forms and shared word-concept relationships. A language’s set of unique lexical concepts is known as the lexicon. The specific sensory elements utilized by language users are surprisingly arbitrary and vary across cultures. Sound and visual symbols are the most commonly used. A language’s auditory and written sensory elements are termed phonemes and graphemes, respectively, and their methods for combining them into words are similarly termed phonology and orthography.
Expressing language requires a communicator to generate an idea they wish to convey (e.g., conceptual preparation), retrieve the lexical concepts that align with the intended content, represent the message as a sensory (e.g., phonological) target, and select the appropriate motor (e.g., articulatory) plan to produce external sensory perturbations that allow a listener to comprehend the utterance.10 Producing language requires some form of motor output—most commonly speaking, writing/typing, or signing—but other methods can be utilized in situations of motor compromise.
Focal nervous system damage can disrupt language functioning in specific sensory and motor modalities while leaving others intact (e.g., pure word deafness, alexia, etc.). In people with language symptoms, it is important to determine if the deficit is modality-dependent (e.g., auditory verbal comprehension vs. reading; speaking vs. writing) or independent (e.g., poor comprehension regardless of sensory input). Modality-specific deficits suggest the potential use of alternative pathways to access—and unlock—hidden linguistic capacities.
Language deficits can disrupt affective and social functioning, often causing frustration, anxiety, withdrawal, and isolation. These reactions are often an appropriate grief response to the acquired reduced ability to communicate specific intentions, desires, and beliefs, and to understand those of other people. While an important means of social engagement, symbolic language is only one of many methods of communication between individuals and may only represent a small portion of the transmitted information between individuals. In addition, the selective loss of language functions may, in some cases, potentiate other nonlinguistic capacities.11,12
In classic aphasiology, the language system is lateralized to the left hemisphere in most people, and grossly divided into a posterior, sensory, receptive region (i.e., Wernicke’s area) in the temporal and parietal lobes, and an anterior, motor-grammatical, expressive area (i.e., Broca’s area) in the frontal lobe, which are connected by the arcuate fasciculus, a white matter tract. Damage to the posterior areas produces poor comprehension of language with spared expressive fluency (Wernicke aphasia), and anterior damage produces poor fluency with spared comprehension (Broca’s aphasia). The ability to repeat is affected in both conditions. This framework serves as a foundation for the remainder of this section (please see Figure 12-1).
Classical aphasiology syndromes. NB: Wernicke and transcortical sensory aphasias are also categorized as a “receptive” and Broca and transcortical motor as “expressive.” + signifies intact; − signifies impaired.
Basic Language Comprehension
Because so many of the formal cognitive tests across multiple domains rely on verbal comprehension, it is important to test the basic integrity of this system. The simplest way is to ask the patient to follow commands. For efficiency, it is sometimes best to begin with longer, more difficult requests (e.g., for those in Boston: “indicate with the fingers of your left hand the number that corresponds to the first letter of the name of the city we are in…”). If the patient manages this challenging task, this faculty is likely intact. If not, the examiner can pursue more elementary components of language processing. Simple, short requests are often useful as they reduce the attentional and working memory demands, a potential confounder. Successful execution of these tasks implies that basic verbal comprehension is intact.
Basic verbal comprehension requires several steps, including specialized sensory processing to decode sensory inputs into language symbols, linking the symbols with the appropriate semantic concepts, and using this integrated information to select an action that communicates understanding. Deficits in any of these steps produce different patterns of impaired language comprehension.
The ability to decode sensory inputs into language symbols is a modality-specific process accomplished within primary and secondary sensory areas (discussed below). The linkage of symbols to meaning is likely a domain-general process occurring within a multimodal convergence zone within posterior parts of temporal lobe (see Chapter 3 in this volume),13 adjacent to high-order auditory and visual processing areas. Injury to this lexical-semantic interface is associated with Wernicke aphasia, which is characterized by reduced comprehension of spoken and written language with fluent verbal output that lacks meaningful content. The patients often demonstrate a striking lack of insight into their own deficits.
The ability to decode sensory inputs into language symbols occurs in secondary unimodal sensory cortices (e.g., audition, vision). Selective disruptions in this process cause comprehension deficits isolated to the affected sensory modality, even when primary sensory perceptions for that mode are intact. Pure word deafness (or auditory verbal agnosia), for example, is characterized by poor comprehension of verbally presented words with preserved reading comprehension and hearing. The patient may even be able to identify and discriminate between basic phonological elements of speech. Speech may be perceived as sounding like a foreign language. This is often caused by damage to phonological processing areas within the bilateral (occasionally unilateral left-sided) superior temporal gyri. Pure alexia (or pure word blindness) is the parallel syndrome within the visual modality where previously-literate individuals can comprehend words presented verbally but not textually, even when the primary elements of vision are normal. They have difficulty with writing. This occurs with damage to orthographic (i.e., visual letter and word representations) processing areas located within parts of the left fusiform gyrus, which is part of the ventral visual processing stream (see below). These conditions suggest a disturbance not in the lexical-semantic interface but instead a selective problem with representing phonological and visual word forms.
Deficits in sensory decoding into language elements can be strikingly focal. The left fusiform gyrus processes increasingly complex forms of visual orthographic representations along a posterior-to-anterior gradient. The mid-anterior fusiform is appropriately known as the “visual word form area” (VWFA), as lesions cause pure alexia. If the posterior fusiform is undamaged in these cases, letter comprehension is spared, yielding the syndrome of letter-by-letter dyslexia.14 This syndrome is characterized by a unique reading deficit whereby affected individuals perceive individual letters but not whole words. To overcome this, individuals read a word’s letters out loud one at a time in sequence until the previously imperceptible word and its meaning are suddenly identified, presumably by utilizing an alternate phonological pathway to access the lexical-semantic interface. Patients with deficits in the visual language pathways important for decoding letter and words have concomitant difficulties spelling words that relay on phonic rules (e.g., reasoning via visual symbol-to-sound relationships).
A nearly identical pure alexia syndrome known as alexia without agraphia can emerge from focal damage to a different set of adjacent regions, namely the left primary visual areas in the occipital cortex and nearby posterior part of the corpus callosum (i.e., splenium). Affected individuals have a right-sided visual field deficit due to the left occipital damage; vision is intact in the left hemifield because the right occipital/visual areas are spared. Because visual information is decoded into language symbols in the left fusiform gyrus, the right occipital cortex sends its visual information across the hemispheres via the splenium of the corpus callosum to be processed for reading. Because the splenium is damaged, the left fusiform does not receive the visual inputs, causing alexia despite intact primary vision within the left hemifield. Because the language network and auditory inputs are spared, verbal comprehension, speech, and writing are intact. A striking and memorable phenomenon occurs whereby the patient writes a sentence but is unable to read what he has written only a few moments later. Neurobehavioral deficits that emerge due to poor information flow between processing areas is known as a disconnection syndrome.15
Because many components of language comprehension are modality-specific, when a deficit is identified it is important to test this system using different sensory inputs (e.g., verbal and written). Difficulties should, of course, prompt an assessment of elemental sensory and motor functions, including testing of basic hearing, vision, and the motor system.
Lexical Retrieval Deficits and Anomia
Highly effective communication depends on the ability to rapidly access specific lexical-semantic concepts and their associated sensory word forms in real time. Once a concept has been selected for expression, the appropriate lexical label (e.g., sensory word form) must be retrieved before it can be expressed as a communicative action. This lexical retrieval process is often guided by top-down (e.g., internally generated) mechanisms, but may be facilitated by exposure to sensory-perceptual features related to the word form or concept (e.g., stimulus-driven). The functional networks supporting this process are complex, and involve regions involved in perception, semantic processing, and directed search capabilities. Please see Figure 12-2, to illustrate this.
Networks involved in naming and lexical retrieval. (Reproduced with permission from Hope TM, Price CJ. Why the left posterior inferior temporal lobe is needed for word finding. Brain. 2016;139(11):2823-2826. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.)
Lexical retrieval deficits commonly present as anomic aphasia characterized by word retrieval deficits in spontaneous speech and difficulty naming objects on confrontational testing (e.g., Boston Naming Test). In spontaneous speech, affected individuals may experience a frustrating “tip of the tongue” state where they can describe the concept they wish to express without being able to recall the sensory (e.g., phonological) word form. They are often able to provide detailed descriptions of ideas they wish to express, or pantomime the use of objects, despite being unable to conjure up the appropriate and specific lexical label. Frequent use of synonyms and other circumlocutionary phrases leads to imprecise and vague-sounding content. Speaking may be interrupted by hesitations or pauses to allow time for word searching. The retrieval difficulties are most apt to occur for low-frequency words. On tests of confrontational naming, providing the first letter or sound of the elusive word often aids its retrieval. The individual is virtually always able to recognize the word from a list of multiple choices. The elusive word may spontaneously come to the speaker after a few moments. Some speakers consciously use methods to aid their word search by providing their own internal phonemic cues by silently imagining each letter of the alphabet. Slips of the tongue can occur, particularly semantic paraphasias, where incorrect but semantically related words are expressed (e.g., “guitar” instead of “banjo”).
In anomic aphasia due to a lexical selection deficit, both the bank of semantic concepts and lexical labels (e.g., the lexicon) are intact, but their connections are disrupted. The ability of concepts to activate their lexical labels becomes less efficient, and requires top-down, frontally mediated search mechanisms or bottom-up perceptual stimulation (e.g., phonemic cues, multiple choices) to facilitate the connection. The strength of concept-label connections varies across concepts; the activation of semantically related concepts with more readily accessible lexical labels leads to semantic paraphasias. In anomic aphasia, the disruption of the lexical-semantic interface is largely unidirectional; perception of sensory word forms (e.g., phonological word forms) efficiently activates the appropriate concepts.
Anomia symptoms are most severe when concept-to-label connections and the compensatory systems become dysfunctional. Problems with decoding language (e.g., phonological processing), semantic knowledge (e.g., reduced number and nuance of conceptual stores), and top-down directed search mechanisms can exacerbate symptoms. These functionally disparate processes seem to converge within the left temporal lobe. Deficits in lexical retrieval in anomic aphasia localize to left lateral temporal regions, including most notably the mid-to-posterior middle temporal gyrus (MTG),17,18 mid-to-posterior inferior gyrus, superior temporal gyrus, and the associated subcortical white matter.19 Semantic paraphasic errors, similarly, occur most commonly with damage to the posterior inferior temporal cortex.20
The MTG is a heteromodal region that processes highly integrated information from multiple sensory processing streams The MTG is situated adjacent to areas known to process semantic/object information, the inferior temporal cortex, and phonological information, the superior temporal cortex. Confrontation naming deficits may be category-specific based on the involved anatomy: objects/noun and action/verb impairments associate with temporal and frontal dysfunction, respectively. The precise mechanisms for this observation are debated, but may relate to category-specific differences in semantic storage, lexical access, or syntactic handling.21
A critical aspect of language processing is the ability to represent and flexibly access semantic knowledge. Semantic concepts are specific, clustered combinations of sensory, motor, visceral, cognitive, affective, and linguistic information that are bound together. A simple concept would be a square, which has specific perceptual quality and a geometrically based definition. The “square” concept is likely to be similar across individuals. An individual’s concept of “baseball,” however, may be more complex. To some, “baseball” encompasses the sensory smell of fresh cut grass and the sound of a fastball “popping” the mitt, motor plans for swinging a bat and throwing a pitch, visceral responses watching ninth inning of the World Series, cognitive rules and strategies, affective elation of winning, and the linguistic knowledge of one’s favorite players, among many others. While there are core conceptual features likely to be shared across individuals, the concept is ultimately individualized. The ability to bind complex, multimodal representations together (such as baseball) and associate them with specific lexical labels allows for efficient communication of complex ideas.
The binding process is conceived like the hub and spokes of wheel. A concept’s hub has specific, weighted connections with many types of information (e.g., cognitive, visceral, perceptual, motor, limbic, etc.), the spokes, that in aggregate comprise the concept. Hubs are located in heteromodal areas, whereas the spokes are located diffusely in multiple locations depending on the representational content. Losing one or two spokes (e.g., visuospatial, lexical representations) does not lead to a complete loss of the concept, although it may be less detailed, as other features may be maintained. Damaging the hub, however, prevents the binding of features into a unified construct, causing a loss of conceptual representations.22
Patients with semantic aphasia have difficulty describing objects in precise terms and tend to offer only vague, tangential replies. Phonemic cues or multiple choices do not improve performance. Their spontaneous speech may be difficult to follow due to its lack of detail, although patients are often not bothered by their diminished verbal precision. These deficits may occur in neurodegenerative disease such as the syndrome of semantic variant primary progressive aphasia (svPPA). Affected individuals usually maintain exemplar representations of categories longer and lose the fine-grained details that are constructed around these prototypes. For instance, when asked to draw pictures of a variety of animals, patients may sketch a series of basic, dog-like animals that lack distinct features central to each animal.23 Patients speak in a similar manner, often using generic, categorical terms in place of more nuanced expressions (e.g., “my wife Anna” becomes “the woman,” “my home in Cambridge” becomes “the place”). Some of these symptoms can also occur in degenerative conditions beyond that of svPPA, including Alzheimer’s disease.
The bedside evaluation for semantic knowledge includes asking patients to name objects, to draw or describe objects in as much detail as possible, or to associate objects with overlapping semantic features. Testing confrontational spelling and oral reading of words can also be informative. Disproportionate errors handling words that do not follow phonetic rules (e.g., irregular words), such as “yacht,” “gnome,” or “choir,” is called “surface” dyslexia and dysgraphia. Knowledge of the linguistic quirks of these words is part of their semantic representation, and when this information is compromised, a common strategy is to rely on phonetic spellings to arrive at the answer.
svPPA is associated with striking atrophy of the left > right anterior temporal lobes. The ventrolateral anterior temporal lobe is widely considered to be the site of the so-called semantic “hub.” However, cases of acute, unilateral anterior temporal damage, or surgical removal of the anterior temporal lobe due to focal epilepsy, are rarely associated with major semantic loss. The functional neuroanatomical mechanisms for this finding are unclear and are vigorously debated. Damage to the “spokes” cause more restricted forms of semantic loss. Parietal lobe damage, for example, can affect one’s previously acquired conceptual and procedural knowledge of how objects work and how they interface with the body, leading to the inability to pantomime learned motor acts (i.e., apraxia).
Deficits in Verbal Working Memory and the Sensory Guidance of Speech
Communicating with language expressions requires individuals to “hold in mind” what they wish to say while simultaneously formulating and executing the appropriate motor expression. This online maintenance of linguistic intention (i.e., the “phonological content buffer”) is critical for continuous, smooth language output. This can be examined by asking patients to repeat phrases of increasing length. It is best to uses phrases that are semantically impoverished or unpredictable (e.g., “Arthur was an oozy, oily sneak”) to prevent one from accurately reconstructing the sentence word-for-word from its semantic content alone. A common type of error is an inaccurate reproduction of phrases that nevertheless communicate the original semantic gist (e.g., “It is a rainy afternoon in Boston” becomes “It is pouring rain today in Massachusetts”). Length-dependent repetition errors often suggest a deficit in verbal working memory or a problem with the linguistic computations occurring within this buffer.
The syndrome of conduction aphasia is characterized by poor verbal repetition accompanied by slips of the tongue (i.e., paraphasic speech errors) despite intact comprehension and fluency. The patient may be unable to maintain longer spoken phrases online. Paraphasic errors are usually phonologically based, including syllable or sound substitutions, deletions, insertions, or transpositions (e.g., shortstop becomes “portstop”), which can sometimes produce neologisms or quirky spoonerisms. These disordered phonemes are produced without articulatory distortions, suggesting intact motor-speech effector functioning. Speech errors are more apt to occur on longer, novel, and phonologically complex phrases, particularly those lacking in semantic content. The logopenic variant of PPA is a degenerative aphasia with many overlapping features with conduction aphasia, including paraphasias during repetition and prominent word-retrieval deficits. Note that successful repetition does not require comprehension to be intact, as one can repeat words without understanding their meaning.
Verbal working memory (the so-called “phonological loop”) is supported by a network that includes the posterior superior temporal cortex and left IFG.24 Immediate “echoic” auditory working memory (lasting a few seconds) occurs in the temporal lobe, and does not require frontal systems.25 Active, online maintenance of verbal information beyond this short timeframe, however, recruits inferior frontal systems important for motor-speech planning. This phonological loop is often conceived as a network supporting “silent rehearsal” of motor speech acts, which sustains specific phonological contents within the verbal working memory store. Damage anywhere along this phonological loop circuit can produce length-dependent repetition errors.
More recent conceptions of the regions involved in verbal repetition have begun to shed light on the computations occurring within verbal working memory stores (see Chapter 3 in this textbook; see also Hickok and Poeppel26 and Leonard et al.27). Based on incoming sensory information received by the listener, primary and secondary auditory processing areas within the superolateral temporal lobes construct phonological representations of word forms (e.g., auditory/sound “images”). During repetition tasks, these auditory images are held in a phonological working memory storage buffer and serve as the “sensory target” for the motor system, whose goal it is to reproduce that sound target as accurately as possible through the appropriate sequencing and execution of motor-articulatory actions. The selection and sequencing of articulatory gestures is performed by motor-speech areas within the left inferior frontal and ventral premotor areas, and ultimately fed forward to primary motor areas located on the precentral gyrus that interface with the articulators via corticobulbar and corticospinal projections.
This process of sensory-to-motor translation, whereby auditory images represented in superior temporal areas are mapped onto appropriate motor-articulatory templates in the left inferior frontal areas, is thought to be mediated by cortical areas within the left temporoparietal junction (TPJ, adjacent to the supramarginal gyrus and superior temporal cortex). Damage to this area causes errors in verbatim repetition and paraphasic errors,28 possibly due to incorrect mapping of phonological targets to the appropriate motor program.
Characterizing aphasia syndromes by repetition skills aids in their categorization and localization. Intact repetition implies intact functioning of the dorsal language stream, which includes phonological encoding (e.g., bilateral superior temporal), sensorimotor translation (e.g., TPJ), and motor planning and execution (e.g., left IFG). The syndrome of poor comprehension with normal fluency and repetition suggests impairment in the ventral language stream, where sensory language symbols are mapped onto semantic networks. If semantic knowledge is intact (i.e., the patient can demonstrate knowledge of concepts that do not rely on verbal information), the problem likely is one affecting the lexical-semantic interface, putatively centered within the MTG and its connections.26,29 This syndrome is termed transcortical sensory aphasia and has traditionally been conceived of as a disconnection syndrome30 caused by white matter tract disruption between Wernicke area and semantic centers, although cortical disruption alone can reproduce the syndrome.29
Motor Speech Deficits and Agrammatism
Expressive linguistic communication requires motoric actions that produce interpretable sensory language symbols. For speech production, this involves central motor-articulatory processes important for planning, initiating, sequencing, and executing phonetic/articulatory actions. Downstream motor effector pathways are responsible for enacting muscle movement plans involved in speech production, and include the upper motor neurons, cranial and peripheral nerves, neuromuscular junction, and muscles themselves. When these distal effector pathways are damaged, they cause dysarthria, which is characterized by articulation errors due to weakness, ataxia, and/or sensory loss.
Commonly reported symptoms of central motor-speech dysfunction include reduced overall verbal output with slow, effortful speech, mispronunciations, dysarthria, apraxia of speech, and stuttering, among others. Mutism can occur in severe cases. The precise pattern of symptomatology depends on the affected neurologic territory. Speech deficits are often readily detected while observing spontaneous speech, although these systems can be taxed by asking the patient to repeat complex, multisyllabic words or phrases (e.g., tongue twisters like “Methodist Episcopalian”).
Successful production of fluent language output requires that an appropriately sequenced, exquisitely coordinated series of complex movements (i.e., articulatory for speech, manual for writing, gestural with signing) unfold with precise timing. Disturbances in any of these elements—sequencing, timing, coordination—or in the processes that regulate them will lead to speech errors. The neural network underlying these processes involve both cortical-subcortical areas, including primary, premotor, and supplementary motor cortices, the basal ganglia, and the cerebellum, as well as their connections with other functional networks (e.g., cognitive, sensory, limbic, etc.). Selective damage to components of these networks tends to yield distinct patterns of aphasia. Similar to language comprehension, expressive-motor deficits can be modality-specific, with speech, writing, and signing differentially affected.
Damage to the bilateral primary motor cortex or its efferent pathway, the pyramidal tract (i.e., upper motor neuron), is associated with the pure speech disorder known as spastic dysarthria. The speech is slow, with a strained, “tight” quality (e.g., as though the throat is being squeezed) due to increased laryngeal muscle tone, and the articulatory movements of the lips and tongue are slow but coordinated. An exaggerated jaw jerk reflex may be elicited, reflecting loss of descending motor control and inhibition of the lower cranial nerve pathways from the cortex. Occasionally there may be pseudobulbar affect (i.e., “emotional incontinence”), the dysregulated and uncontrolled expression of emotion that often does not reflect the patient’s internal state, also presumably is due in part to loss of corticobulbar innervation of emotion-organizing centers in the brainstem. See Chapter 8 in this textbook for further discussion of pseudobulbar affect and its treatment.31,32 Because most of the lower cranial nerve nuclei that control guttural movements receive bilateral innervation from the primary motor cortices, unilateral lesions are unlikely to cause a severe spastic dysarthria with a strained quality. Asymmetry in tongue protrusion33 or facial muscles can occur with unilateral damage, however, which can cause a selective and often mild lingual or buccal dysarthria. The time course of onset for spastic dysarthria varies and can develop acutely due to bilateral opercular strokes (e.g., Foix-Chavany-Marie syndrome34), chronically in neurodegenerative disease (e.g., amyotrophic lateral sclerosis, primary lateral sclerosis, progressive supranuclear palsy), and others in between.
Damage to the motor planning areas causes apraxia of speech, a condition characterized by effortful speech, inconsistent articulation errors, poor initiation, unanticipated speech errors with attempts at self-correction, stopping and starting “trial and error” corrections (aka “groping” speech), and abnormal prosody, among others.35 Apraxia of speech occurs with disruption of motor-speech planning networks: the lateral premotor areas (e.g., ventral and dorsal) are important for sequencing, and medial premotor areas (e.g., supplementary motor area) for timing and initiation. Ventral premotor areas within the posterior aspects of the left inferior frontal cortex (i.e., posterior IFG, rostral precentral gyrus, anterior insula) contain developmentally acquired sensorimotor articulatory-motor programs that encode specific movement sequences for specific syllables or words.36 Lesions here produce articulatory distortions and other speech apraxia symptoms in cases of acute stroke37 or the degenerative syndrome of primary progressive apraxia of speech.38,39 Other studies place the lesion critical for the development of primary progressive apraxia of speech more superiorly in the dorsal premotor areas and supplementary motor area.40 In severe cases, there may be a total inability to speak despite intact writing and oropharyngeal functioning, which some have labelled aphemia, although there is no consensus on how this term should be used.41
The canonical expressive aphasia that affects all expressive modalities (i.e., speaking, writing, signing) is Broca’s aphasia, which is characterized by reduced language output (i.e., nonfluent) and poor repetition with relatively preserved comprehension and other aspects of cognition.42,43 The reduced expressive output is not explained by weakness. This impairment is often accompanied by agrammatism, in which patients do not produce nor comprehend sentences that rely on syntactic structures to convey their meaning (e.g., “The lion was eaten by the tiger—which animal is alive?”).44 Speech may be “telegraphic,” where only content words (e.g., nouns, verbs, adjectives) are used, and function words such as articles and prepositions are omitted (e.g., “I want a Skittle” becomes “I want Skittle”). Apraxia of speech may also be present. Many of these symptoms are most pronounced during spontaneous, propositional speech, and fluency may improve during overlearned, automatic speech tasks such as singing, counting, and reciting the days of the week. Not surprisingly, patients with Broca’s aphasia often appear frustrated and exasperated while speaking. Many of their language faculties are spared, such as single-word comprehension, intention, semantic processing, and lexical retrieval. Patients may report a normal-sounding internal monologue, suggesting spared phonological encoding (i.e., sensory targets). The deficit lies in the normally effortless translation of their linguistic intent into grammatically appropriate expressions within the motor-articulatory system.
Broca’s aphasia is seen with disruption of the left IFG and several of its surrounding structures. This connected set of regions is known as “Broca’s complex.”45 Broadly speaking, Broca’s complex is critical for shaping language ideas into hierarchically organized grammatical structures and preparing them for motor expression. Multiple functions support this process, including accessing and holding online phonological and other sensory language representations (e.g., lexical retrieval, verbal working memory), grammatical processing, and translating these structures into exquisitely timed and sequenced motor plans for overt expression (i.e., articulatory planning). The posterior inferior frontal gyrus and surrounding areas play a critical role in packaging of verbal output in accordance with appropriate word order (syntax), phrase structure, and use of grammatical morphemes (such as word endings that modify tense or number). Disruptions of these processes will lead to focal deficits.
Verbal working memory and directed lexical retrieval (e.g., word generation), for example, are supported by the left IFG and its connections with the parieto-temporal areas. Deficits in this network will produce symptoms of losing one’s train of thought and difficulty generating words without bottom-up supports. Grammatical processing similarly is mediated by the left IFG and disruption leads to difficulty producing and comprehending sentences, with symptoms of telegraphic speech. Motor-articulatory planning relies on premotor systems, with ventral areas biased toward sequencing and dorsal medial areas (SMA) for timing and initiation. Deficits in these systems lead to speech apraxia, stuttering, and in severe cases, speech arrest, sometimes known as aphemia.46 These functions are supported by subcortical connections, including parts of the basal ganglia, thalamus, and cerebellum. This language production network connects more broadly to cognitive, limbic, and other areas. In this light, Broca’s complex is best conceived of as an integrative hub for expressive language that facilitates the flow of information across multiple language subsystems47,48 and its interface with other broad systems (e.g., cognitive, limbic, etc.).
Damage to Broca’s area “proper,” a more restricted cortical location within the posterior IFG corresponding to Brodmann area 44/45, is associated with relatively mild deficits in fluency (speaking in short sentences), agrammatism, and occasionally, a foreign accent syndrome. The foreign accent syndrome is a motor speech disorder where one’s speech changes from their normal dialect and takes on a “foreign” sound quality, often occurring after neurologic injury. The etiologies are can be divided into functional (i.e., psychogenic) and structural. Structural etiologies (strokes, tumors, TBI, multiple sclerosis, etc.) tend to occur in the frontal lobes (or other perisylvian language/motor/sensory areas; the cerebellum may also be involved), often including different aspects of Broca’s complex that is important in fluency, grammar, articulatory planning (e.g., timing, sequencing), and prosody (e.g., stressed/unstressed syllables).
Language expressions contain much more than symbolic references to semantic concepts and their hierarchical relationships. Speech is infused with emotionality, social nuance, metaphor, inference, and connation. These aspects are critical for effective social communication through language, known as pragmatics. The addition of stressed and unstressed sounds, melodic contours, intonation, variation in volume, rhythm, and others to convey additional social communicative meaning is known as prosody. Diminished or inappropriate prosody is known as aprosodia, or dysprosody. Dysprosody can present as comprehension or expressive deficit. This syndrome may develop after damage to the nondominant hemisphere, often within the perisylvian areas, although this localization is controversial.
The Language System’s Interaction with Intention
A different type of motor-speech disorder, dynamic aphasia (i.e., transcortical motor aphasia), is characterized by a marked reduction in spontaneous propositional speech.49 These individuals have difficulty initiating and maintaining self-generated speech, have difficulty engaging in conversation, and appear to lack the impulse to speak. They may be misdiagnosed with depression despite insisting on a normal internal mood state. Formal language testing usually reveals intact comprehension, confrontational naming, repetition (including lengthy utterances), and grammatical processing. Different clinical subtypes of the dynamic aphasia syndrome have been described, including those with language-specific deficits (e.g., verbal planning) or domain-general processes (e.g., conceptual preparation).50 The deficit can occur as part of a mixed aphasia syndromes. The symptoms often reflect disrupted connections of language system with other cognitive (e.g., executive skills) and affective systems (e.g., motivation).
Dynamic aphasia emerges with disruption of a network involving dorsal medial prefrontal areas,51,52 the left IFG, their subcortical connections, and their interconnected white matter tracts.53 The dorsal medial wall of the posterior frontal cortex houses two anatomically adjacent areas, the supplementary motor area (SMA) and pre-SMA. These areas have important connections with cognitive and motor systems and play an important role in self-initiation and energization of thought and action.54,55 SMA connections with the left IFG play a critical role in speech timing, initiation, and monitoring56; pre-SMA-IFG connections provide a link between intention/motivation and language expression.53 The pre-SMA may contribute to spontaneity in verbal expression. The white matter pathway connecting dorsomedial prefrontal cortices and the IFG is known as the frontal aslant track.57 Reduced integrity of these fibers is associated with deficits in spontaneous propositional speech58 in individuals with the nonfluent variant of PPA, a dementia syndrome associated with phenotypic features similar to Broca’s aphasia.
The Language System Is an Example of the Broader Concept of Praxis
The motor-articulatory system represents a specialized example of a broader skill set: the execution of complex, learned motor actions (i.e., praxis). Apraxia is the “inability to correctly carry out purposeful, skilled movements when this deficit is not caused by elemental motor or sensory deficits, abnormal involuntary movements, or cognitive disorders.”59 Skilled motor performance requires knowledge about how self-generated actions impact the body and the environment, which is learned iteratively through repeated actions, error detection, and feedback. Through experience, specific actions become associated with predictable sensory consequences, forming stored sensory-motor representations. Selection and activation of these sensorimotor programs in appropriate context supports the unfolding of complex, learned, purposeful actions. Examples include swinging a baseball bat, hammering a nail, playing the guitar, and others. These sensorimotor associations are stored as connected networks between posterior parietal and premotor cortices, often supported by subcortical network connections, with posterior areas encoding sensory-perceptual representations and frontal areas specific motor programs. These programs are subject to bottom-up, more “automatic” activation and top-down, “goal-directed” activation.60 Apraxia occurs when these sensorimotor programs are damaged or are not accessed properly.
Acquiring these complex, specific sensorimotor representations requires a more immediate mechanism for perception-acting coupling. The so-called “mirror neuron” system matches combinations of perceptual inputs with the specific frontal motor systems most likely to accurately reproduce those inputs61; these relationships may be formed by experience during developmental sensorimotor learning.62 Examples of this sensory-to-motor integration include verbal speech perception connecting with motor articulatory areas to guide speech mimicry, or visual perception of another’s limb movements connecting to motor limb-kinesthetic areas to support action mimicry, or seeing a picture and drawing it. Enacting these perceptually driven action representations leads to overt sensory consequences (e.g., visual, proprioceptive, somatosensory, etc.) that are fed back into the action-perception model, setting the iterative learning process into motion.
Activation of these sensorimotor pathways is subject to top-down and bottom-up regulation. Loss of top-down regulation of these systems can produce disinhibition of the mirror neuron system,63 leading to echophenomena, including the automatic mimicry of sounds, known as echolalia, or movement, echopraxia. Loss of bottom-up activation may lead to reduced mimicry and reduced imitative learning, as is seen in individuals with autism.64
The neural correlates of certain types of apraxia mirror those of aphasia. In both cases, perceptual inputs facilitate the selection and execution of specialized motor sequences, although in one the target is primarily auditory (i.e., spoken language), and in the other is visual-kinesthetic (i.e., limb movement). In limb praxis, three-dimensional visual-kinesthetic sensory targets are learned and stored as sensory programs and are used to guide the selection of actions to be planned and executed by the frontal lobe. These stored sensory targets, known as engrams, are stored in parieto-temporal regions and are connected to modality-specific (e.g., limb, oro-buccal) premotor areas in the frontal lobes involved in motor planning. An individual’s learned set of engrams is known as the “praxicon” (similar to “lexicon” in the language system). These parieto-frontal connections support the appropriate selection of specific motor programs that enact the visual-kinesthetic engram. This parieto-premotor learned action sensorimotor network is also connected with medial prefrontal areas (e.g., SMA) important for initiation and timing of the movements. Dr. Kenneth Heilman has offered an apt metaphor of playing the piano: the parietal cortex contains the sheet music that provides the sensory codes, the frontal cortex represents the piano player that executes the content of the sheet music, and the primary motor effectors represent the piano itself (Dr. Kenneth Heilman, 2017, Harvard-Longwood Grand Rounds). Damage to the engram-containing regions in the parietal lobe leads to ideomotor apraxia, whereby individuals have difficulty knowing how to posture their limbs when executing a previously learned action generating the sensory images of the action they have previously learned.59 Limb-kinetic apraxia, whereby the precise sequencing and timing of limb actions is poor, occurs with damage to frontal structures.59 Other types of apraxias are described, including ideational, constructional, and others.
This entire process is strikingly similar to the sensory guidance of speech. Given the overlapping peripheral anatomy required for speech articulation and other oro-buccal actions (like sniffing a flower or blowing a kiss), and the somatotopic cortical representations of these areas within the primary and premotor cortex, it is not surprising that lesions within the inferior frontal areas that cause expressive aphasia also tend to cause oro-buccal, and sometimes limb-kinetic, apraxia. In these frontal lesions, the more posteriorly located sensory targets (e.g., engrams) are spared, and accordingly, patients are usually able to identify the correct learned motor movement, even if they are unable to execute them properly.59
Figure 12-3 provides a schematic summary of cortical language processing and the clinical syndromes that may result from disruption of its different components.
Summary of cortical language processing.
Expected Speech/Language Syndromes
A—Pure word deafness with phonological paraphasias; spared oral reading and reading comprehension
B—Pure alexia, malformed letters/words (?orthographic paraphasia); spared verbal comprehension
C—Repetition errors (length-dependent), phonological paraphasias (worse on long/complex words), naming errors, neologisms; intact comprehension of single words
D—Poor word deafness (i.e., verbal comprehension deficit) without phonological paraphasias; intact repetition and semantic concepts
E—Apraxia of speech (variable misarticulations, groping speech, stuttering; ?also writing), poor initiation/spontaneity, agrammatism, aphemia (when only affecting speech programs), pure agraphia (when only affecting writing programs)
F—Semantic loss, surface dyslexia
G—Agrammatism, telegraphic speech, loss of functor words
H—Dysarthria (type depends on lesion location)
A−D = “Wernicke”; E+G = “Broca”; C = “conduction”
? = putative role or anatomical location
CHARACTERIZING DEFICITS AFFECTING EPISODIC MEMORY
One of the most common presenting symptoms in clinical settings is “memory loss.” When this is the chief complaint, one must keep an open mind about the potential cognitive systems involved, as patients and families often use the term “memory” colloquially when referring to other aspects of cognition, including lexical retrieval, visuospatial dysfunction, apraxia/agnosia, and attention problems, among others. Even when formal “memory” testing is abnormal (e.g., the ability to recall a recently learned word list), the differential diagnosis includes both executive/attentional and memory processes, each of which is supported by distinct functional neuroanatomy and has its own list of potential etiologies. The precise characterization of memory deficits can determine its underlying localization and uncover consequential diagnostic, prognostic, and sometimes therapeutic information.
Memory is a broad term describing many different cognitive processes that share the property of retaining or recreating information to which the person was previously exposed. The ability to store aspects of experience allows one to adapt to a changing environment. This broad concept encompasses both explicit/declarative processes that are directly accessible to consciousness, such as episodic and autobiographical memory (e.g., replaying the content of prior experiences) and semantic memory (e.g., factual and conceptual knowledge of the world), and implicit/non-declarative process such as procedural memory (i.e., the execution of learned, complex motor actions; “tying shoes”), associative learning through operant conditioning (i.e., emotional reactions such as fear with exposure a triggering stimulus), or the effects of priming (e.g., recent exposure to a stimulus influences the response to a subsequent, related stimulus, a process not dependent on conscious intention or guidance). Brain dysfunction can impact all of these processes, although the circuits underlying each vary.
Memory may be broadly conceived of as a modulator of neural predictions, by which prior inputs exert influence over how ongoing inputs are processed, including perception.65 Memory stores are strengthened by the salience of the inputs and their behavioral consequences.
Mechanistically, the neurotransmitter dopamine is an important modulator of neuroplasticity and learning. Its presence within synapses facilitates long-term potentiation (LTP), an important cellular mechanism for stabilizing and strengthening specific neuron-to-neuron connections.66 Many of the brain’s dopamine-releasing neurons originate in the ventral tegmental area (VTA) of the midbrain, an area activated by different types of detected environmental salience.67 Widespread areas of the brain receive dopaminergic projections, including the prefrontal cortex, the hippocampus, and striatum. The salience-triggered release of dopamine may help to guide the brain to store inputs that are most behaviorally relevant. The neuroanatomical location of the dopamine release may support different types of memory, including the motor striatum for procedural motor learning, the ventral striatum and amygdala for emotional learning (e.g., desire/anticipation, fear), and the hippocampus for episodic memory.68 Non-dopamine neurotransmitter systems also impact memory storage mechanisms, including acetylcholine, norepinephrine, and others.
Episodic memory refers to information acquired at a specific time, place, and circumstance (e.g., what one had for lunch yesterday), and includes the sensory, motor, cognitive, emotional aspects of experience. Some examples include remembering and reliving the memory of watching the Red Sox win the 2004 World Series, what was ordered for lunch at the hospital cafeteria yesterday, or the details of a recent conversation with my mother.
Patients with episodic memory deficits—commonly referred to as amnesia—have difficulty recalling information about prior experiences, or even that particular events occurred at all. In severe instances, such as reported in the famous case of H.M.,69 patients are completely unable to consciously recall information obtained even a few minutes earlier. When repeatedly exposed to similar circumstances, patients behave as though the experience is novel, reacting to others with surprise and treating the situation as unfamiliar. The ability to update longitudinal self-schemas and personal narratives is disrupted, as is the passage of time, yielding the phenotype of being “stuck” in a particular time period and way of relating to the world. Personal insight into these deficits is usually poor. Episodic memory may be lost for events occurring prior to a single point in time, known as retrograde amnesia, and/or after a point in time, as in anterograde amnesia.
Complete, permanent episodic memory loss is relatively rare, but can occur in conditions that cause damage to the temporal lobes bilaterally, such as limbic encephalitis (e.g., herpes simplex virus, autoimmune conditions, many others) and traumatic brain injury. Transient global amnesia, a fascinating and somewhat enigmatic clinical syndrome, is characterized by acute-onset complete episodic memory loss that usually resolves within several hours. The pathophysiologic mechanisms underlying the disorder are debated, but MRI often demonstrates transient signal abnormalities within hippocampus70 or perihippocampal structures.
Symptoms of partial amnesia are common but may be subtle, often manifesting repetitive behaviors such as retelling stories and asking the same questions, forgetting details of prior conversations or story plots, misplacing items, increased reliance on lists to keep track of information, among others. Prospective memory, the ability to remember the timing and nature of future engagements, may also be affected.71 Time sense can be altered, including when an event took place, how long it lasted, the sequential order of happenings, or its temporal sequence in relation to other events. Place information is often affected, including where an event took place, or what the scene looked like. The ability to remember when and where information was obtained is known as source memory.72 Insight into one’s own amnestic symptoms may be preserved in mild cases.
There are several ways to quantitatively test episodic memory function and learning. Tasks that rely on short-term processes (e.g., minutes) can be administered in a single office visit, allowing for a rapid assessment of these functions. Most learning protocols follow a similar series of steps: (1) exposure to new information/stimuli, (2) immediate confirmation that the information was absorbed (i.e., encoding), (3) distraction and the passage of time, (4) testing spontaneous recollection of the presented information (e.g., retrieval), and (5) assessing recognition of the information when provided clues/hints (e.g., storage). The stimuli that are used vary across tasks and may include word lists, stories, pictures/figures, word and shape associations, or the physical locations of objects hidden in a room.
Episodic memory is often conceptualized as a three-stage process: (1) encoding, (2) storage, and (3) retrieval. The 5-step bedside memory testing protocol described above allows one to isolate—at least operationally—the processing stages supporting memory formation (see Figure 12-4). The neuroscientific accounts of the stages supporting memory formation are more nuanced, detailed, and complex than what is discussed below. The discussion provides a starting point for more comprehensive assessment.
Schematized 5-step protocol to test memory functions. Schematized 5-step protocol to operationally isolate the memory stages of encoding, storage, and retrieval. The conclusions drawn assume that other cognitive functions known to affect memory performance (e.g., language comprehension to understand the instructions, sustained attention, effort, etc.) are controlled or otherwise accounted for.
An individual with difficulty demonstrating immediate retention of recently presented information is said to have deficits in encoding. If, after a period of distraction, they are unable to spontaneously recall the previously presented information, they have either a deficit in storage or retrieval. If the individual can recall the information with cues or recognize the information when presented multiple choices, the deficit is considered one of retrieval. If the individual does not improve with cues or choices, the deficit is one of storage. While this oversimplifies a complex process, it nevertheless provides a conceptual schema to frame memory processing.
Encoding is the process whereby experiential information (e.g., sensory, cognitive, emotional, etc.) is engaged by attentional and working memory systems and prepared for short-term storage. Patients unable to demonstrate their retention of newly presented information moments after the instruction is provided (and comprehended) are said to have encoding deficits. This may occur with dysfunction in attentional and working memory systems and their connections with mesial temporal and hippocampal areas. Experiential information (i.e., a multisensory perceptual traces) needs to be perceived and transformed into a format that can be stored, accessed, and re-instantiated later. This process depends on perception and attentional processing mediated by fronto-parieto-subcortical areas73 and the memory areas subserving data preparation for storage in the mesial temporal/hippocampal areas.74–77
Storage deficits prevent the formation and retention of new episodic memories. Providing contextual cues does not readily facilitate the recall of information, which is unlike retrieval deficits. Storage deficits result from damage to the hippocampus, its local inputs (e.g., parahippocampal gyrus), or its connections along a larger limbic network (i.e., the Papez circuit—see Figure 3-8, Chapter 3) including the cingulate cortex, fornix, mammillary bodies, subiculum, and anterior thalamus.78 These temporolimbic structures index experiences for later recollection and support encoding and storage. Streams of highly integrated information from sensory, cognitive, affective, and other systems—the online contents of experience—are filtered, stored, and indexed by these structures, including their occurrence at a particular time and place. Content to be remembered is selected based on its degree of salience. People tend to remember important life experiences in rich detail such as their wedding day, the birth of their children, the death of loved ones, personal traumatic experiences, or major cultural events. Flashbulb memory is a term used to describe the detailed memory of where a person was and what he was doing when he learned about a major event,79 such as the 9/11 attacks, JFK’s assassination, or the OJ Simpson verdict.
Recalling these stored streams of highly integrated information lets one replay and reexperience them by recapitulating their expression within perceptual areas, and their spatiotemporal markings allow one to order past events in the proper sequence at the appropriate locations.80 Minor deficits in the storage system may limit the vividness of the recollection or cause uncertainty about when and where an episode occurred; major deficits cause a complete absence of recall. Wernicke-Korsakoff syndrome, characterized by profound amnesia with confabulation and poor insight, is associated with injury to parts of the temporolimbic system (e.g., mammillary bodies, anterior thalamus), and is caused by thiamine deficiency, often in people with alcohol dependence81 or prior bariatric surgery.82 Patients with Wernicke-Korsakoff syndrome may unintentionally produce false statements or engage in false behaviors that are reflective of inaccurate memory or belief, a symptom known as confabulation.
Episodic memory loss due to temporolimbic dysfunction tends to spare memory for remote events that occurred months and years ago. Remote memories often take on the character of semantic memory, becoming grounded more by their factual content and less by their experiential vividness. These remote events become stored as semantic knowledge in cortical networks outside the hippocampus. This observation was made famous in the case of H.M., who was able to recall autobiographical events from his early childhood despite a total loss of more recent events. A similar dissociation with sparing of memory for remote events occurs in the early stages of typical Alzheimer’s disease, a degenerative condition affecting mesial temporal structures and associated with short-term episodic memory storage loss.
Access to episodic memory stores can occur via top-down, goal-directed directed retrieval (e.g., during formal memory testing) or through bottom-up, stimulus-driven mechanisms triggered by ongoing perceptual experiences (e.g., hearing a song on the radio triggers the memory of one’s first kiss).83 Goal-directed, top-down retrieval of recently presented information is supported by fronto-parietal-subcortical structures and their connections with mesial temporal memory areas.83,84 Deficiencies in these active retrieval processes can be overcome with cues and multiple choices, which provide a robust bottom-up stimulus as alternative pathway to activate the prior memory stream. If the patient cannot give the correct answer in this aided setting, despite having successfully encoded the information earlier, the problem is believed to reflect deficient storage mechanisms.
The consequences of poor retrieval are significant. Memory traces inaccessible by top-down processes cannot be used to guide explicit, goal-directed behaviors, and leads to ill-informed decision making. Retrieval is essential for everyday functions such as remembering internet passwords, the car’s location in the parking lot, or the events that occurred at a meeting. As part of the default mode internet linking motivationally relevant, internally generated, top-down processing areas in the medial prefrontal cortex with the mesial temporal episodic memory areas,85 this retrieval system allows us to reexperience past events flexibly and on demand (see Chapter 3 of this volume).
CASE VIGNETTE 12.1
Mr. L is a 73-year-old right-handed man with past medical history of hypertension, hyperlipidemia, and sleep apnea, who initially presented with 2−3 years of progressive word-finding difficulties. His difficulty finding words is associated with circumlocutions, word substitutions, paraphasic errors, vague speech, and mild comprehension difficulties in which he asks others to clarify their utterances immediately after they speak. Other, non-language symptoms include reduced concentration and mild memory deficits. He is functionally independent.
His elemental neurologic examination is notable for mild paratonia and awkward rapid alternating movements on the right side. Neuropsychological testing demonstrates multidomain cognitive impairment, including language, executive functions, and verbal memory. His language deficits include poor confrontational naming, reduced generative fluency (semantic > phonemic), length-dependent repetition errors, and phonological paraphasias. His auditory verbal memory is much worse than his visual verbal memory, and was impaired at all levels (encoding, storage, and retrieval). His brain MRI reveals global atrophy, left more than right, with disproportionate involvement of the temporal, parietal, and dorsal parieto-frontal areas. There is a mild burden of microvascular disease as evidence by FLAIR hyperintensities. Cerebrospinal fluid analysis shows no clear evidence of inflammation. He has reduced beta-amyloid and elevated total and phosphorylated tau levels.
Mr. L has a mild neurocognitive disorder, and his symptoms localize best to dysfunction within the phonological loop (left posterior superior temporal sulcus, temporoparietal junction, left inferior frontal gyrus, arcuate fasciculus) and, to a lesser extent, dorsal frontoparietal attentional and executive control networks, and temporolimbic memory storage areas. His clinical diagnosis is mild cognitive impairment with logopenic language features. The most likely underlying etiology is neuropathological Alzheimer’s disease.
CHARACTERIZING DEFICITS AFFECTING ATTENTION
The particular thoughts, feelings, or sensations that illuminate one’s momentary subjective experience seem to reflect the internal gaze of one’s attention. The seemingly limitless possibilities of conscious experience momentarily collapse into rather constrained chunks of subjectivity. The processes that engage, disengage, filter, select, switch, inhibit, and maintain the elements of experience comprise the mechanisms of attention.86
The brain’s perceptual neural machinery is frequently repurposed in the name of efficiency. The same areas that represent incoming sensory information as perceptions of external reality (e.g., the tree in front of me right now) are also used to imagine past perceptual experiences (e.g., the tree I walked past last week) or to mentally simulate (i.e., “embody”) semantic concepts (e.g., the concept of a tree). The mode of engagement may shift based on the behavioral context and the priorities of the individual. Detected environmental salience may redirect resources toward specific sources of incoming sensory information; a quiescent environment may shift toward internally generated stimulations for learning or preparation; other times, it is useful to explore the external environment for potential resources or threats. Flexible shifting between modes of attentional engagement optimizes the brain’s limited resources.
Modes of Attention: Stimulus-Driven (“Bottom-Up”), Goal-Directed (“Top-Down”), and Stimulus-Independent (“Default Mode”)
The detection of salient stimuli in the environment causes a rapid reallocation of attentional resources directed toward the stimulus. This “bottom-up,” involuntarily, stimulus-driven system alerts and reorients perceptual systems to help assess the relevance, value, or meaning of a stimulus or event. If one is reading a book, for example, and is suddenly bit by a mosquito on the arm, attention may immediately shift from the story plot to the arm and an accompanying interest in the precise location of the bite, the identification of the bug, and a seemingly involuntarily quick slap. According to some models of attention, this rapid reallocation of neural resources is correlated with activity in a cortical network known as the ventral attention network (VAN), which includes ventral frontal and parietal regions, namely the IFG and the TPJ, and tends to be lateralized to the right hemisphere (see Figure 3-2B, Chapter 3).87 The VAN is strongly connected with cortical and subcortical areas important for decoding salience from incoming sensory inputs. Activity in the VAN may encode subjective awareness of attentional shifts and/or provide signals that alter activity in other attentional networks. When a salient, bottom-up signal activates the VAN, attentional resources are shifted toward the incoming stimulus.
Attention may also be directed by top-down, goal-directed processes. Consider the example of looking for a lost set of keys. When searching, one maintains the goal of finding the keys while directing attention and eye movements to various spatial locations within the space, biasing each upcoming location to recognize the visual pattern suggestive of keys. Directed spatial exploration, where attention is directed to information at specific locations, is supported by activity in the dorsal attention network (DAN), with hubs located in the dorsal and lateral parts of the parietal (e.g., the intraparietal sulcus, IPS) and the frontal (e.g., frontal eye fields, FEF) lobes bilaterally.87 Some investigators also include parts of the MTG in the DAN. Both the IPS and FEF contain egocentric (i.e., self at the center) spatial maps of the external environment.88 The DAN supports shifts in spatial attention involved in the visual exploration of the environment and generating expectations about incoming information for a particular location.89
When unexpected or potentially relevant behavioral information is detected outside the DAN-prioritized spatial locations, the right TPJ becomes active as part of the VAN. TPJ activation marks the occurrence of bottom-up, stimulus-driven changes in attention, and supports an orienting response; right TPJ strokes impair the spatial orienting.90 The VAN may be important for switching between other large-scale networks (e.g., default mode, central executive) when unanticipated salient changes are detected,91 although this may also be supported directly by the broader salience network (see Chapter 3). Violations in the expected sensory consequences of actions, uncued changes in context, and the perceived beginnings and ends of behavioral events92 are known to activate the right TPJ, all of which may provide an impetus to initiate changes in top-down attention and goal-directed behaviors.
The DAN and VAN have important interactions and they share a hub in the right middle frontal gyrus. The set-point for VAN-associated attentional shifts can be downregulated by tasks requiring a high degree of top-down attention. Professional basketball players shooting free throws, for example, are able to suppress opposing fans attempts at distraction (e.g., fans yelling their name and waving signs behind the hoop), likely reflecting suppression of the VAN. VAN activity also temporarily changes activity in the DAN.
During periods of environmental quiescence, attention can be directed away from immediate external environmental salience and toward internally generated mental states. Processes such as mental simulation and rehearsal, imagination, episodic memory recall, self-talk, and others may help prepare one for future situations, learn through analyzing prior experiences, and develop mental models to understand the world. These processes may be goal-directed or triggered by spontaneously generated internal stimuli. These internal triggers may be salient to the individual. This attentional state is supported by the so-called “default mode” network (DMN), with anatomical hubs in the medial and lateral parietal, medial prefrontal, and middle temporal cortices (see Figure 3-4 in Chapter 3).93 The DAN and its companion, the central executive network, may coactivate with the DMN to support purposeful recollection or directed mental simulation.
Focal behavioral symptoms occur when these networks are damaged or dysregulated. Disruption of the DAN is associated with reduced top-down, goal-directed processing, and produces symptoms distractibility, loss of intention, and excessive environmental reactivity. Disruption of the VAN leads to reduced adaptability to salient changes in one’s situation.
Dysfunction of the DAN and VAN has important clinical consequences. Hemispatial neglect is characterized by a lack of awareness and inability to attend to egocentric space to the left or right of the vertical meridian. This occurs with acute damage to the nondominant (usually right-sided) hemisphere, often involving the parietal lobes, but also frontal or subcortical areas. When severe, neglect symptoms extend beyond the visual sensory modality, impacting somatosensory and auditory processing, motor intentions, and cognition, including exploratory behaviors and mental simulations. Broadly speaking, these patients lose awareness of the existence of a world beyond the left side of their egocentric vertical meridian. They may not eat food on the left side of their plate, not move their right hand beyond midline when asked to reach for their hemiparetic left hand, and be unable to generate a mental map of the United States west of Chicago. They may not acknowledge hemiparesis affecting the left side of their body (i.e., anosognosia), deny ownership of their own left-sided body parts (i.e., asomatognosia), or harbor the delusion that the left side of their body must be someone else’s (i.e., somatoparaphrenia).
Hemispatial neglect may also be subtle, and when incomplete, may only become apparent with the introduction of competing stimuli on the non-neglected side, typically the right. This can be tested by providing double simultaneous stimulation on both sides of the patient’s hemispace. If patients perceive the stimuli when tested individually on each side, but report only right-sided events with simultaneous stimulation, they are said to have extinction, a sign of unilateral neglect. Other methods include asking patients to copy figures or draw a clock, bisect a horizontal line, cross out with a pen all instances of a symbol (such as a line) on a page, or describe a map of their state or county. When severe, hemispatial neglect can be easily mistaken for a hemianopia (i.e., unilateral visual field deficit, most often due to primary visual cortex damage) and may be indistinguishable at the bedside.
Neglect associated with damage to the right parietal areas often affects both DAN and VAN machinery, although the TPJ and its white matter connections with the frontal lobes may be most critical.94 This typically occurs with right-sided lesions and not with damage to the left. This supports the notion that the right hemisphere is important for bilateral spatial attention and the left hemisphere only for right-sided attention; damage to the right hemisphere, it follows, results in an unopposed attentional bias toward the right side of the egocentric world by the left parietal lobe.
CHARACTERIZING DEFICITS AFFECTING EXECUTIVE FUNCTIONING
Executive functioning is critical to organizing and sustaining goal-directed behaviors. These skills facilitate appropriate decision making in response to changing environmental demands. The ability to select and shift the contents of one’s top-down attention (i.e., attention control) and ignore others (i.e., inhibitory control), to set and sustain behavior goals/targets, provide a cognitive platform for planning and manipulating complex mental actions (i.e., working memory), select among competing actions (i.e., conflict resolution), and monitor their outcome are some of the important operations of executive functioning.
Patients with executive dysfunction present in myriad ways, and the condition is often labeled simply as the dysexecutive syndrome. Symptoms of losing one’s train of thought or purpose for engaging in a task may reflect poor working memory; difficulty with planning or staying organized may suggest reduced cognitive flexibility; distractibility, impulsivity, and difficulty finishing tasks may reflect poor vigilance or inhibitory control; errors in judgement or reduced insight may suggest poor conflict and internal monitoring, respectively.
The executive functions, like other aspects of the cognitive state examination, are hierarchical; it is important to test working memory early as impairments in this capacity may markedly impact the performance of other skills. Simple tests of working memory include a digit or spatial span. Processing speed can be assessed with a Stroop color naming task or Trail Making Test Part A (TMT-A). Cognitive flexibility and task switching can be examined with the Trail Making Test Part B (TMT-B) or the Wisconsin Card Sorting Testing. Response inhibition can be assessed with anti-saccades, Stroop color-word interference task, or a go/no-go task. Generative fluency may be used to assess energization and initiation. Please see Chapter 5 (Neuropsychiatric Assessment) and Chapter 7 (Neuropsychological Evaluation in Neuropsychiatry) for further discussion about testing of executive functions.
Executive functioning has traditionally been considered to be primarily supported by the prefrontal cortex, although more recent conceptions extend the neural regions involved to include the parietal cortex and subcortical network encompassing the basal ganglia, thalamus, and cerebellum. The “central executive network” (CEN) includes regions of the prefrontal cortex, including the dorsolateral prefrontal cortex (DLPFC), frontopolar cortex, orbitofrontal cortex, dorsal anterior cingulate cortex (ACC), as well as the superior and inferior parietal, temporal, and subcortical areas.95 Damage anywhere along this network can impair functions associated with executive control.
A complete discussion of the particular contributions from each node of the network, or of each of the executive skills individually, is beyond the scope of the chapter. A few examples of executive functions are highlighted below.
Working memory is what allows us to hold a thought, an image, or sound—or any conscious perception—in the mind actively and continuously. It permits one to hear a phone number and keep it “online” for a few moments before dialing it, or to retain the image of one’s surrounding visual environment immediately after closing the eyes. This active maintenance process has a limited storage capacity; for example, most individuals cannot immediately recall word-for-word the script of a 2-minute television ad after watching it once, or the step-for-step choreography of a dance performance. Some suggest working memory capacity to be limited to four bits of information; others suggest seven plus or minus two. How the basic perceptual content is “chunked” and held online is critical for how they are utilized by the brain for other purposes. Working memory is an essential building block for so-called “higher-order” cognitive skills, including many aspects of executive functioning important for analytical reasoning and multistep processing (see below), real-life aspects of language such as engaging in conversation and reading, and long-term memory storage, among other skills. It is thus critical for goal-directed behavior, including the skill of maintaining a goal online.
Other conceptions of working memory extend its meaning to include both the temporary storage capacity and a superimposed central executive component. Information held online is transformed through cognitive operations, and this entire process is termed working memory. This conception of working memory can be tested using tasks that require maintenance and manipulation, such as spelling words backwards or performing serial calculations.
Working memory deficits manifest symptomatically as difficulty retaining information immediately after it is presented,96 and occur when the systems important for holding information online are dysfunctional. With disruption of auditory or verbal working memory systems (i.e., the “phonological loop”), patients cannot hold verbal information in mind, and may report that they forget what they had planned to say, that information “goes in one ear and out the other,” or that they have difficulty comprehending long phrases. They may need to write things down to recall the information later. When the deficits affect visuospatial information (i.e., the “visual sketchpad”), patients cannot actively maintain recently presented visual information online. Working memory deficits associated with impairments of executive control may present as difficulty managing complex multistep tasks, deficits in problem solving, and difficulty with mental math.
The neurological systems that underlie working memory systems are discussed elsewhere in this textbook (see Chapter 3). In general, working memory requires the online maintenance of neural representations, which include both a mental “image” to be sustained (e.g., a recently presented sound, image, touch, etc.) and a mechanism for sustaining it. The mental images are sensory representations supported by visual, auditory, somatosensory, and multimodal cortices within the parietal, temporal, and occipital cortices. Active maintenance of these sensory images and its resistance to interference is subserved by dorsolateral prefrontal areas. Any pathological process affecting these fronto-parietal-subcortical networks can cause the syndrome of working memory impairment.
Working memory capacity can be tested by asking patients to hold increasingly lengthy bits of information. For auditory systems, a forward digit span or repetition of sentences are easily quantifiable methods. The visual systems can be probed using a “spatial span” test where the examiner points to different spatial locations sequentially and the patient is asked to repeat the same sequence. The number of locations to sequence becomes larger with each successive trial.
Sustained Attention and Impulsivity
The reduced ability to voluntarily sustain one’s attention on a goal-directed task is referred to as poor vigilance. Common symptoms include difficulty concentrating and maintaining focus, distractibility, not completing tasks, and excessive mind-wandering. Vigilance testing employs tasks that require prolonged engagement without taxing other higher-order executive functions, to isolate the skill of interest. A prolonged “go/no-go” test, such as Connor’s Continuous Performance Task, in which the patient responds to a target stimulus and withholds a response to foils, is a standard approach. A bedside testing example includes counting backwards from 100 to 0 by threes. The functional neuroanatomy of vigilance is complex97 and likely represent the dynamic interplay between top-down and bottom-up attentional control systems.98 Vigilance deficits can emerge with dysfunction of frontal and/or parietal areas that often involve the right hemisphere and/or ascending neurotransmitter systems (e.g., acetylcholine, norepinephrine, others). These systems are often disrupted in states of toxic-metabolic encephalopathy or delirium.
The ability to inhibit one’s prepotent, automatic responses to stimuli is an important aspect of executive functioning. This braking function affords the opportunity to consider the consequences of impending actions and decisions. Reduced inhibitory control is a common symptom in attention-deficit hyperactivity disorder, which may be associated with impulsivity (e.g., blurting, talking out of turn, impatience, overeating, risky behavior) and hyperactivity (e.g., fidgety, “can’t sit still”). The mechanisms underlying these symptoms are complex and generally felt to result from dysfunction within cortical-subcortical network involving the orbitofrontal cortex, right lateral inferior frontal cortex, striatum, and thalamus.
The environmental dependency syndrome is a behavioral syndrome characterized by excessive utilization and interaction with the contents of one’s immediate environment.99 This can manifest with echophenomenon, the tendency to involuntarily mimic observed behaviors, including speech (“echolalia”), gesture (“echopraxia”), and facial expressions (“echomimia”). The neural underpinnings are likely complex and potentially multifactorial; they can develop in states of reduced inhibitory control or reduced self-monitoring as can occur with disruption of bilateral frontal circuitry in conditions such as degenerative disease, catatonia, Tourette syndrome, and others.
Other Executive Functions
The DLPFC may also may be involved in holding evaluative “rules” or goals on-line,100 and selecting among potential competing behavioral responses. Deficits in inductive, rule-based cognition can occur with DLPFC damage.101
The dorsal ACC contributes to cognitive control by detecting conflict. This can be examined at the bedside with a Stroop interference task, where individuals are presented written words of colors that are printed in different ink colors and asked to name the ink color instead of reading the word. The ACC receives widespread input from multiple networks, including the salience network, DMN, and others. The ACC’s detection of conflict applies to a wide range of representations, including between competing motor programs, the outcome versus the expectations of actions, or even between a task-demand and one’s sense of capacity to carry it out.
CHARACTERIZING DEFICITS AFFECTING VISUOSPATIAL FUNCTIONS
The cortical visual system is anchored by the occipital cortex, with primary visual areas surrounding the calcarine fissure at the occipital pole, and higher-order aspects of visual processing (e.g., color, depth, motion, object/pattern representations, etc.) supported by adjacent sites within the occipital, parietal, and temporal areas. The visual system is broadly conceptualized as being composed of two “streams” of information processing (see Chapter 3). The ventral “what” pathway, which includes the fusiform gyrus inferiorly and the occipito-temporal cortices laterally, is important for representing and identifying visual patterns important for object recognition, face recognition, reading of text, and other functions. It serves as the visual system’s most direct pathway to semantic networks. The dorsal “how” (or “where”) pathway, located within the superior occipital, lateral parietal, and lateral frontal cortices, uses visual information to create spatial representations that guide attentional resources and motor actions. The ventral and dorsal pathways are connected at various points along their streams, which may allow for the integration of different representations. Similar to other sensory systems, as visual information moves away from the primary visual cortex through the stream, information becomes more highly processed and is integrated with information from areas outside the visual system.
Visuospatial deficits can produce a large variety of symptoms—ranging from cortical blindness to writing deficits to clumsiness when reaching—depending on which aspect of the visual system is affected.
Not being able to see represents the most basic, and profound complaint about visual processing. Blindness can occur with lesions anywhere within the afferent visual system, including the eye and its related structures (e.g., cornea, lens, vitreous, retina), optic nerve, thalamus, subcortical white matter (e.g., “optic radiations”), and primary visual cortex. When there is concern for blindness, a clinical evaluation for lesions in these precortical areas is required, including a detailed ophthalmologic examination (e.g., visualization of the retina, optic disc, and other ocular structures) and a detailed elemental neurologic examination that specifically measures acuity, confrontational visual fields, pupillary responses, and extraocular movements. For a discussion of cortical blindness and blindsight, please see the section on sensory perception.
Some patients who experience sudden bilateral occipital lobe dysfunction will present with what is easily mistaken for an acute confusional episode. Patients may have difficulty navigating and may walk into walls or closed doors, or they may make references to seeing objects in front of them that are not actually there. The examination, however, is not suggestive of global encephalopathy (e.g., reduced arousal or hyperarousal, poor attention) or receptive aphasia (e.g., inability to follow verbal commands), but unexpectedly reveals cortical blindness. This condition goes by the eponym Anton-Babinski syndrome, and is characterized by cortical blindness accompanied by a lack of awareness of visual deficits (e.g., anosognosia), confabulations of visual content, and the delusional belief of intact vision despite contrary evidence.
The Dorsal Visual Stream: The Visual System’s Contribution to Spatial Aspects of Cognition and Action
The dorsal stream of the visual system—the superolateral extension of the visual system into the parietal and frontal lobes—is fundamentally responsible for representing the world as a three-dimensional, extrapersonal space with the self existing at the center. The dorsal stream is where the brain computes representations of depth and distance, left and right, and relational concepts such as “in front of,” “behind,” “above,” and “below.” These spatial representations are utilized by other systems to guide movements, direct attention, and enrich or support aspects of cognition.
The elemental aspects of dorsal stream processing—depth, orientation, spatial relationships, locations—can be examined at the bedside. A basic screening test for these functions is to copy or mimic visually presented information with limited semantic content, a skill referred to as constructional praxis. Successful performance implies intact perceptual and constructive functions, which are supported by posterior aspects of the dorsal stream (e.g., perception) and their connections with frontal-premotor cortices, important for motor planning (e.g., construction).102 The Rey-Osterrieth Complex Figure Test requires individuals to copy as accurately as possible a complex, multifeatured line drawing103; many other figures exist, including intersecting pentagons and a Benson figure.102 See Chapters 5 and 7 for further discussion of testing of visual function. Mimicry of complex bimanual hand shapes (e.g., interlocking “A-OK” signs) can also be used.104 Other tests of dorsal stream functions include the number location subtest of the Visual Object Spatial Perception (VOSP) battery, where one is asked to determine which number in an upper square corresponds to the same location of a dot in a lower square, the Judgement of Line Orientation test, and the Hooper Visual Organization Test. Of note, poor performance on these tests can result from non-visuospatial processes, including attention/concentration, planning/organization, and motor skills.
The ability of sensory systems to guide action selection is a recurring theme in behavioral neurology and has broad implications for how experience-driven predictive models influence action, thought, and behavior, as discussed below.
Understanding Sensory-Guided Movements
One of the central functions of the dorsal visual stream is to make visuospatial information useful to cognitive and motor systems. It serves as the blueprint for transforming visual sensory information into specific actions performed by frontal systems. Take the example of seeing and reaching out to pick up an apple. The frontal cortex has access to a large number of motor programs, many of which are learned and stored as an array of prepotent programs. Picking up the apple requires that a highly specific series of movements be selected (termed “action selection”) that achieve a specific spatiotemporal outcome (termed “action specification”), as determined by the behavioral context.
All movements generate sensory feedback, and through repetition and experience, the brain learns to associate specific movements with specific sensory consequences. These learned sensorimotor associations become bidirectional: internally generated actions generate sensory expectations (e.g., feedforward control) and bottom-up perception of specific sensory patterns automatically activate the motor plans associated with those sensory percepts, as occurs in the so-called “mirror” system.105 Top-down mechanisms can activate the same sensorimotor system: goal-driven selection of specific sensory outcomes (e.g., action specifications) activates the specific action plan predicted to produce the target sensory outcome.5,106 In the case of picking up the apple, the action specification target is the specific visual and tactile sensation associated with reaching and grasping, which is then used to select the appropriate reaching and grasping movements associated with those sensory consequences.107
In a given context, there are likely many possible action specifications and overt actions that are possible. Inputs from cognitive (e.g., the apple is soft) and evaluative (e.g., the apple is ripe and delicious) systems may influence the action specifications and selections, ultimately yielding a decision about the motor plan to be executed.
This sensorimotor system is subject to feedback control. Actions selected based on their expected sensory consequences may not yield the expected results, possibly due to poorly tuned sensorimotor associations or errors in motor execution. The mismatch between the expected and overt sensory consequences produces an error signal which is used to select corrective actions.
The intended sensory targets, the overt feedback, and error calculation all occur in the dorsal stream via connections between parietal and prefrontal cortices. In the case of picking up an apple, when the selected action yields erroneous consequences (e.g., the arm reaches to an incorrect location), the mismatch error is detected in the sensory systems and a new, updated sensorimotor action plan is engaged to correct it (e.g., adjust the reach).
Disturbances in these visuomotor circuits produce visually guided motor deficits. When affecting limb movements, these errors manifest clinically as clumsiness in reaching, causing symptoms such as knocking things over or mispouring glasses of water, among others. The reaching functions can be assessed at the bedside by having the patient make a pointer with his index finger and reach out and touch the end of the examiner’s similarly extended finger, preferably near the extent of the patient’s reach. Deficits will manifest as slow but smooth, imprecise reaching movements to the target, often reaching beyond the target; this is a finding known as optic ataxia.108 The mechanisms for this are likely myriad, including the poor spatial mapping of actions, altered depth perception, or an overreliance overt visual feedback (as opposed to feedforward) for motor control.
Deficits in visually guided eye movements can also occur, manifesting as difficulty surveying or scanning the visual environment with ease and difficulty bringing into focus objects in the visual periphery, among others. On exam, patients have difficulty moving their eyes rapidly toward a visual target (i.e., saccades) or pursuing a moving target across their visual field. They may only be able to volitionally move their eyes slowly and with great effort, or may need to close their eyes before initiating the movement, or they may turn their head without moving their eyes within the orbit. This cluster of signs is known as oculomotor apraxia (historically labeled “psychic paralysis of gaze”). This may be due to problems generating an egocentric spatial grid of the world, a function supported by the lateral parietal lobes, resulting in difficulty computing where objects are located in space. The lack of spatial coordinates results in poor visual sensory targets, thereby affecting the eye movement plans via abnormal signaling through the parieto-prefrontal pathway.109
The sensory-to-motor guidance of action is not isolated to the visual modality. Broadly speaking, there are multiple sensory areas within the lateral temporal-parietal areas (i.e., auditory, visual, somatosensory; often heteromodal) that are richly connected with effector-specific (e.g., articulators, limb, eyes) motor planning areas in the frontal lobe that together form a circuit supporting sensory-guided action. These circuits carry specific names: the “phonological loop” for phonological guidance of speech; the frontal and parietal eye fields for sensory guidance of eye movements; the “praxicon” or visuo-kinesthetic engrams for praxis-related movements. For speech processing, see Hickok et al.110
These strong, bidirectional sensorimotor, perception-action pathways offer a potential mechanism to explain a diverse set of mental phenomena beyond the guidance of overt skeletal muscle movement. The abstract notion of tightly coupled action-perception associations whose activity is driven by context via top-down or bottom-up mechanisms can extend to internal mental phenomena. Activating these frontal/action and parietal/perceptual networks offer a mechanism for representing simulation of episodic memories (i.e., prefrontal-hippocampal-parietal circuits), imagination, mental rotation, scene construction, and aspects of working memory.
It is possible that activation of these sensorimotor associations is important for tagging experiences as belonging to “self.” When actions are selected by central processes, they contain both a movement and sensory expectation. If these connections become disturbed, selected actions become unyoked from their sensory associations and the action-driven incoming sensory information is falsely (but understandably) interpreted as coming from the external world as opposed to the action. When dovetailed with faulty belief evaluation systems, this mismatch persists and leads to reduced feelings of agency or ownership over movement. While the neural construction of these complex self-related phenomena is likely more complex than what is presented here, these principles of sensorimotor integration are important.111 This model has broad implications for disease states, including alien limb phenomena where affected individuals report a reduced sense of agency over their limb movements, and elements of psychosis, including delusions of self (e.g., somatoparaphrenia) and hallucinations. Alien phenomenon is often reported with parietal and frontal lesions.112,113
Other Dorsal Stream Functions
The inability to integrate the individual elements of a visual scene into a bound-together, coherent whole is known as simultanagnosia. In this condition, patients are unable to integrate visual elements at different levels of their attentional zoom, possessing an inability to “see the forest for the trees.” This skill requires integration of multiple stimuli occurring at different spatial locations and depends on the ability to shift attention/gaze and to hold perceptual content in working memory while it is bound together. The disrupted neuropsychological mechanisms are debated but may entail a “restricted spatial window of attention,” somewhat akin to how a spotlight can produce an intense effect on a small spatial area or weak effect across a broad area, but not both simultaneously, deficits in object perception, or the interaction between both of these systems (i.e., object perception guiding spatial attention).114 Others have suggested a combination of deficits in visual exploration and shifting of spatial attention, visual short-term memory, and visual speed of processing.115
Performance of this cognitive skill can be assessed in several ways. Asking the individual to describe the elements of a scene containing multiple, related simultaneous “happenings” at different spatial locations requires them to shift their attention to integrate the components into a broader whole. The Cookie Theft picture from the Boston Diagnostic Aphasia Examination or the Picnic Scene picture from the Western Aphasia Battery are two commonly used stimuli. Patients with simultanagnosia may fixate on a single aspect of the picture or be unable to combine the components into a larger narrative. Another test involves identifying all instances of a single letter that are presented in different sizes among alternative letter choices. Affected individuals are apt to perceive only the smallest letters that can be processed by focused attention and single fixations, but miss the largest letters, whose perception requires widening the attentional window and/or attentional shifts. This pattern of deficit is the opposite as one might expect from reduced visual acuity. This form of visual processing can also be tested using Navon figures, where a larger, recognizable shape (such as a letter) is composed of smaller copies of a different shape (a different letter, or number). Patients with simultanagnosia are unable to perceive the larger shape despite intact recognition of the smaller component. Simultanagnosia is associated with lesions in the bilateral parietal and occipital areas.
The Italian Renaissance-era painter, Giuseppe Arcimboldo, is well-known for his art that portrays tactfully arranged fruits and plants that create hierarchical images of expressive human faces (see Figure 12-5). Perception of these faces requires the ability to perceive larger visual structures composed of smaller individual elements. Deficits in this processing ability lead to simultanagnosia and can develop with bilateral occipito-parietal lobe injury or dysfunction. In viewing Arcimboldo’s paintings, patients with simultanagnosia may not perceive the face despite seeing the individual fruits.
Examples of hierarchical visuospatial forms. The Italian Renaissance-era painter, Giuseppe Arcimboldo, is well-known for his art that portrays tactfully arranged fruits and plants that create hierarchical images of expressive human faces. Perception of these faces requires the ability to perceive larger visual structures composed of smaller individual elements. Deficits in this processing ability lead to simultanagnosia and can develop with bilateral occipito-parietal lobe injury or dysfunction. In viewing Arcimboldo’s paintings, patients with simultanagnosia may not perceive the face despite seeing the individual fruits.
When optic ataxia, oculomotor apraxia, and simultanagnosia occur together, it is labeled Balint syndrome. Patients suffering from this condition may report not seeing things located directly in front of them (“I couldn’t find the doorknob,” “I missed the giant TV in the house”). Balint syndrome can occur with bilateral parieto-occipital damage due to any number of etiologies, including stroke, anoxic brain injury, traumatic brain injury, and neurodegenerative disease.
Other testable functions of the parietal lobes include skills in number processing116 and the ability to perform mathematical calculations,117 finger gnosis (e.g., perception of the positioning of one’s finger in space),118 distinctions between left and right, and writing skills. When these functions are disturbed concomitantly, the constellation of symptoms is referred to as Gerstmann syndrome, which is characterized by dyscalculia, finger agnosia, left-right confusion, and dysgraphia.119 Gerstmann syndrome is traditionally associated with lesions of the left inferior parietal lobule (typically the angular gyrus), although the unifying neuropsychological function relating these skills is not entirely clear. It has also been reconsidered as a disconnection syndrome.120 When all of these symptoms are observed along with alexia, anomia, and constructional disturbances, the pattern of deficits has been labeled the angular gyrus syndrome.
There are also dorsal stream connections with memory areas within the mesial temporal lobe and hippocampus via the posterior cingulate and retrosplenial cortices (PCC/Rsp), as part of the so-called parietal-mesial temporal pathway.109 Deficits in this pathway can produce deficits in visuospatial navigation—particularly the type that relies on using landmarks for guidance—known as topographic disorientation. The hippocampus plays a critical role in indexing spatial locations for later recall and recognition. Damage to the hippocampus (and adjacent parahippocampal areas) is associated with poor learning and recognition of spatial landmarks, but a preserved ability to produce mental maps based on self-referential, “egocentric” coordinates (e.g., left-right, forward-back, etc.).121 Damage to the PCC/Rsp, however, leads to a different type of topographic disorientation where patients can recognize landmarks but cannot use this knowledge to inform egocentric navigational decisions.122 This may be due to the PCC/Rsp’s role in linking externally referenced, “allocentric” locations to egocentric spatial representations, as the former is primarily supported by the mesial temporal lobe and the latter by lateral parietal cortices.
A person’s ability to construct a mental map can be tested at the bedside. Asking patients to explain how to navigate from their house to a well-known location in their city, or to draw a map of their home, for example, may offer a window into the cognitive processes at play. Interpreting these narratives is limited; an accurate report does not exclude the possibility that the patient is describing routes from rote memory, and an inaccurate report may be due to deficits in other cognitive domains (e.g., expressive language, memory, etc.). Firm conclusions as to the underlying processing are problematic based on these bedside tests (see Aguirre and D’Esposito123). Reduced navigational skills are a common early symptom of Alzheimer’s disease, which often affects both the mesial temporal, PCC/Rsp, and lateral parietal areas.
The Ventral Visual Stream: Generating Form Based on Salient Visual Patterns
Patients with dysfunction of the ventral visual processing stream present with symptoms and signs that are quite different from those of the dorsal stream. The ventral stream, which extends from the primary visual cortex anteriorly along the inferior occipito-temporal cortices, is where visual information is extracted and decoded into patterns with particular significance or meaning. The computational processing of this pathway allows for the specialized perception of faces, written text, objects, mathematical symbols, and others, and links these perceptions with semantic representations.
An important symptom of ventral stream dysfunction is alexia (i.e., inability to read) or dyslexia (e.g., difficulty with aspects of reading). As mentioned in prior sections, the processes of decoding visual information into orthographic language symbols (e.g., letters, words) occurs primarily within the fusiform gyrus. The fusiform subregion important for the decoding of whole words is known as the “visual word form area.” Damage anywhere along this pathway can cause symptoms of dyslexia.
Dyslexia can result from abnormal visual processing of letters or an inability to link visual language symbols (e.g., orthography) with the appropriate vocal sounds (“decoding”), regardless of the ability to link written words with semantic networks. Errors in these processes are referred to as “deep” dyslexia. Affected individuals may be unable to read non-words or functor words, both of which are semantically empty. When asked to read the word “glove,” they may read it as the semantically related word “mitten.” When asked to spell, individuals with deep dyslexia may be able recall and generate written words based on previously learned semantic-symbol relationships but not use letter-sound relationships as guidance (i.e., phonics), and write “mitten” for “glove.” “Surface” dyslexia, in contrast, is characterized by difficulty reading despite intact symbol-sound relationships. Correct reading of irregularly spelled words (e.g., YACHT, PINT) requires access to these words’ semantic nodes, where information about their linguistic irregularities is stored. When access to semantic information is disrupted, as can occur with left anterior temporal lobe damage, patients rely on phonics as a strategy to read, which leads to errors.
Spelling deficits, a reduced ability to generate written words composed of learned collections of written symbols (e.g., letters), may co-occur with dyslexia. Surface dysgraphia, which occurs with reduced access to a word’s semantic network, is characterized by spelling deficits occurring on irregularly spelled words (e.g., CHOIR, ALIGN), as patients rely on phonetic rules as strategy to spell (e.g., “QUIER” or “ALINE”).
Prosopagnosia, the inability to perceive and recognize individual faces, is associated with focal damage within the right fusiform gyrus in a region appropriately referred to as the “fusiform face area.” This capacity can be tested at the bedside in several ways, including showing pictures of famous faces (and non-famous control faces) and asking individuals to identify them (e.g., by name, stating facts about them, etc.). Human face perception requires the ability to rapidly decode many features simultaneously to produce the feeling of recognition. In prosopagnosia, semantic knowledge of the person whose face is not visually recognized is often intact and can be accessed via other modalities (e.g., gait, gesture, voice, etc.).
Ventral stream dysfunction can cause deficits in the visual perception and recognition of objects. This can be tested by asking patients to name visually presented objects (e.g., using line drawings from the Boston Naming Test). This can be confounded by deficits in lexical retrieval, which can be circumvented by providing cues or multiples choices, or asking the patient to describe the object or to pantomime its use.
The ventral stream has important interactions with attentional and limbic systems. The ability to recognize facial expressions and interpret emotional content in body language, and to detect biological motion (e.g., movements produced by animate organisms) are all supported by ventral stream processing. Attentional and affective regulation can influence the content of the ventral stream perceptions. Conceptual priming, where exposure to specific semantic information unconsciously lowers the activation thresholds for activating other related semantic concepts, alters the perception of incoming visual information, biasing it toward the primed concept. This is distinct from perceptual priming, whereby exposure to certain perceptual forms biases incoming information to more rapidly perceive those and related forms. These inputs can modulate the processing of information within the ventral stream and can generate expectations about the content—and meaning—of incoming percepts.
An interesting example of how top-down regulation of the ventral stream signaling influences the content of visual perception is face pareidolia. Pareidolia is finding meaning in otherwise innocuous, noisy incoming visual signals; it is the idea behind, for example, seeing the face of Jesus in a pancake. There is evidence that the top-down influence of the orbitofrontal cortex on the fusiform gyrus may underlie the phenomenon in some cases.124
Interactions between Visual and Memory Systems
The notion of two separate streams—the dorsal and ventral streams—is likely overly simplified, as there is cross-talk between the two systems at different levels. There are many tasks that activate both pathways simultaneously. For example, when a frisbee is tossed toward a person, he/she needs to produce a visually guided movement plan to catch or avoid it (dorsal stream) as well as identify the object accurately (ventral stream), which informs the best movement selection (dorsal stream). Misperceiving the frisbee’s spatial location or speed, or its identity (e.g., as a porcelain plate), will produce an inappropriate response. Communication between the two streams can be assessed clinically. Individuals administered the Hooper Visual Organization Test, for example, are asked to identify and name objects that are presented as line drawings cut into multiple pieces whose components are displayed at different orientations. This task activates both dorsal (mental rotation) and ventral (object perception) stream visual processing areas simultaneously.125
Humans are able to replay prior experiences in their mind’s eye, which reflects our capacity for episodic memory. Stored episodic memory traces are reconstructed within widely distributed perceptual networks to reproduce a rendition of the prior experience. This is supported by connections between mesial temporal episodic memory centers and perceptual areas. The medial parietal lobe (e.g., the posterior cingulate cortex and retrosplenial cortex), as part of the default mode network, may help mediate this process. Damage to the posterior cingulate cortex leads to deficits in episodic memory and the ability to describe imagined scenes.126
The medial parietal region also supports representations of familiarity, in which patients report a feeling of having previously interacted with a stimulus, even if the precise details of the prior interactions cannot be recollected. Deficits in familiarity are an important component of the delusional misidentification syndromes. The Capgras syndrome, for example, is characterized by the delusional belief that a loved one has been replaced by an identical-appearing imposter, may be driven by reduced familiarity signals associated with the loved one’s face accompanied by an impaired ability to judge the plausibility of one’s conception. Recent evidence suggests disruption in a network that includes the left medial parietal cortex and right inferior frontal lobe.127
Visual Systems and Representations of Self
Dorsal stream machinery, with the support of vestibular, proprioceptive, somatic, and auditory information, acts to situate individuals at the subjective center of their personal visuospatial universe, and represents one’s conscious stream of imagery as unfolding from a single vantage point—the location of “I”—at any given moment. These hardwired, egocentric perspectives are critical in the formation of self-representations. Abnormalities within the dorsal stream, particularly within the right parietal lobe, can disrupt the feeling of automatic self-positioning, leading to symptoms such as out of body experiences,128 autoscopy (perception of the environment from a non-egocentric perspective),129 and a loss of depth perception.
A BRIEF NOTE ON THE LOCALIZATION OF EMOTIONAL, SOCIAL, AND BEHAVIORAL SYMPTOMATOLOGY
This chapter’s primary focus has been on the traditionally classified elements of cognition (e.g., language, praxis, memory, attention, executive functions, visuospatial skills) and not on feeling states, social behavior, personality, and motivation. This asymmetric emphasis in content risks perpetuating the great schism between cognition and affect, thinking and feeling, and neurology and psychiatry, which is the product of longstanding sociocultural influences dating back to the early 20th century.130 While the subjective experiences of emotion and thought are often starkly different, their fundamental neuroscientific underpinnings are similarly reliant on the cellular biological properties of interacting neurons and glia that act in concert across distances to form network-based representational architectures. The anatomy supporting both phenomena are deeply interconnected in the brain at many levels. Even a superficial understanding of human behavior necessitates the integration of cognition and affect; a distinction between the two is artificial.
On a practical level, negative affective symptoms are common, distressing, and often the most proximate reason why people visit the doctor. In patients with memory loss, for example, it is often the feelings of worry that motivates the patient (or family) to seek medical attention. Many patients will only seek help for their limping gait when their knees start to cause pain, or when they become frustrated by their reduced walking speed or other functional limitations. It is critical to recognize the importance of emotional processing in guiding behaviors.
How the nervous system detects, evaluates, and responds to salience in the environment offers the potential to meaningfully integrate perceptual, motor, cognitive, social, and affective processing under a unified framework. These different aspects of human mental functioning are highlighted in Chapter 2 and discussed throughout this textbook.
The phenomena that comprise human experience and behavior are intimately connected to the structure and functioning of the brain. The notion that intricately timed electrical impulses traveling across complex networks of neurobiological circuitry represent and construct the incredible diversity of mental states is the great axiom of cognitive neuroscience and lies at the foundation of neuropsychiatry and behavioral neurology. The organization of this hierarchical biological system supports the many different aspects of human cognitive functioning. Focal neurobehavioral syndromes emerge when these systems are disrupted. This chapter has reviewed some of these basic structures and the symptoms that develop when damage is incurred.
SUMMARY AND KEY POINTS
MULTIPLE CHOICE QUESTIONS
Which of the following is true regarding language dysfunction?
Production deficits can only be caused by disruption of frontal lobe areas.
Comprehension deficits can only be caused by disruption of temporal and/or parietal areas.
A deficit in speech comprehension is always accompanied by a similar deficit in reading comprehension.
Spastic dysarthria is caused by deficits in motor speech planning areas.
Damage to the fusiform gyrus can produce letter-by-letter alexia.
Which of the following is false regarding episodic memory?
Amnesia can occur with herpes encephalitis.
Episodic memory is an important component of one’s autobiographical memory.
Difficulty spontaneously (i.e., without cues or multiple choices) recalling a recently learned word list only occurs with temporolimbic dysfunction.
Memory encoding and storage are supported by temporolimbic structures.
Not all patients with Alzheimer’s disease have memory loss.
Which of the following symptoms is not considered part of the dysexecutive syndrome?
Losing one’s train of thought
Poor decision making
Which of the following is not a function supported by the ventral visual processing stream?
Smooth reaching movements to a target
MULTIPLE CHOICE ANSWERS
Within the fusiform gyrus is the so-called visual word form area (VWFA), where orthographic representations of whole words are represented. Damage to this region cause pure word blindness, a form of pure alexia with spared verbal comprehension. Some patients overcome this by spelling the words one letter at a time to presumably access the word form via an alternative, possibly auditory pathway. (a) Production deficits can occur with damage to the dominant (usually left) temporoparietal junction, as can occur in a conduction aphasia. Affected individuals have difficulty repeating complex phrases and make a high number of paraphasic errors. (b) While single-word comprehension is predominantly subserved by temporal > parietal structures, sentence and grammar comprehension uses inferior frontal systems. (c) Comprehension deficits can be domain-general (e.g., affecting both spoken and written inputs), as in the case of Wernicke and transcortical sensory aphasia, or domain-specific (e.g., affecting one modality but sparing others), as occurs in pure word deafness or pure alexia. Spastic dysarthria is caused by disruption of the bilateral corticobulbar tracts involved in the peripheral motor effector pathways.
Assuming the patient was able to encode properly, poor spontaneous recall recently learned information can result from a deficit in either storage or retrieval. A storage deficit implies temporolimbic dysfunction, whereas retrieval deficits more commonly occur with frontoparietal networks disruption. (a) Herpes simplex encephalitis often affects temporolimbic structures in the mesial temporal lobe, and significant amnesia is common. (b) Autobiographical memory refers to memories related to one’s personal narrative, including prior experiences stored as episodic memories. Semantic self-knowledge (i.e., one’s birthday, or first word) may be autobiographical but not episodic. (d) This is true. (e) While episodic memory loss is a common symptom of typical Alzheimer’s disease, in atypical cases the pathology affects other networks (e.g., visuospatial areas) while sparing the temporolimbic structures, preserving memory function.
Hemispatial neglect usually occurs with disruption of neural areas important for mapping the world onto egocentric spatial coordinates, usually within the nondominant hemisphere. It does not typically cluster with the dysexecutive syndrome. (b−e) These symptoms are all part of the dysexecutive syndrome, which occurs with disruption of the executive control networks.
The use of visual information to guide reaching movements to a target is a canonical function of the dorsal stream. (a−c) The use of visual information to identify patterns that can be linked to semantic networks is the primary function of the ventral stream. These functions include reading, face recognition, and object recognition, among others.
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