144
9
The primate prefrontal cortex (PFC) is most developed in humans and enables integra- tion of recalled past experiences to implement the most appropriate motor response.
These molecular processes are based on pyramidal cell activity and their networks that may occur in the absence of external stimuli. Dopamine is the principal neurotransmitter involved, but is part of a fragile process susceptible to error. Even minor changes in the brain’s neurochemical milieu can lead to network failure. The inverted U- shaped curve of too much or too little dopamine leads to failure. These prefrontal cortical functions are particularly prone to physiological processes such as arousal, fatigue, or stress, as well as external or environmental influences. Hence PFC function is inherently capricious and is considered an Achilles heel in our cognitive abilities. However, these brain areas are particularly plastic and network connections can be strengthened or inhibited rapidly and so provide great flexibility in the behavioral repertoire. These relatively volatile prefrontal functions and vulnerabilities also confer unique human mental disorders. Understanding these mechanisms supports interventions such as meditation and cognitive behavioral therapies that “brain build,” in addition to pharmacological options.
The Human Connectome: Macroscopic Hardwired
145 The Human Connectome
route connects to the subcortical components, the amygdala, hypothalamus, and nucleus accumbens, which mediate emotional responses. The right inferior PFC effectuates inhibitory responses [3]. Together these major circuits guide high- level decision- making, behavior, and emotional responses in a relatively stress- free environment augmented by the ascending monoaminergic fiber tracts. The latter have optimal levels of effect in an inverted U- shaped fashion [4,5]. The amygdala also connects to the brainstem and hypothalamus. With elevated stress, a surge in noradrenaline and dopamine release occurs which has the effect of hindering PFC function and “top- down control,” result- ing in impaired working memory, attention, and appropriate inhibitory responses. A bottom- up, amygdala- controlled process takes over, together with the sensory cortices, whereby stimuli that are visual, auditory, or somatosensory- related predominate. This becomes a more emotive and reflexive response as opposed to a slower, more calculated response [6,7].
In addition to the major cerebral networks discussed in Chapters 3 and 4, the princi- pal cerebral neurochemical tracts include the fast- acting excitatory (glutaminergic) and inhibitory (GABA)-ergic amino acid- type neurotransmitters. There are also eight (dopa- mine, serotonin, norepinephrine, acetylcholine, histamine, oxytocin, vasopressin, and orexin) slower- acting modulatory neurochemical tracts that are “wired” differently. They arise from the brainstem, hypothalamus, and basal forebrain, and have widely projecting ramifications delivering more diffuse, slower- acting, and longer- lasting actions promul- gated by the G- protein cascade that transduces the signal from these neurotransmitters.
This chemical architecture allows the coordination of many neurons, as well as many neuronal circuits in response to a particular threat.
DLPFC network activity is due to pyramidal cell firing that is modulated by GABA, termed lateral inhibition. Goldman Rakic’s research has shown that these interneurons (chandelier and basket cell types) will induce a neuron to fire during the delay period
(a) (b)
Figure 9.1 Prefrontal and amygdala circuits and stress. The brain may be switched from reflective (left) to reflexive behavior (right) in response to stress.
Reproduced by permission from Springer Nature from Arnsten AFT. Stress signaling pathways that impair prefrontal cortex structure and function. Nat Rev Neurosci 2009;10:410–422.
that follows a particular stimulus. However, due to what has been termed “spatial tun- ing,” the pyramidal cell neuron firing has a preference in one direction as opposed to another direction (for example, 90- degree versus 270- degree orientation). This consti- tutes the neural basis of spatial working memory or representational information. The pyramidal cell networks are found predominantly in layer three, are connected with each other by NMDA dendritic synapses, and have the ability to fire in the delay period [8].
This circuitry, with its spatial tuning capacity, can be amplified by dopamine. Another neurochemical process that can augment pyramidal cell firing and connectivity to bolster working memory is calcium.
There is a differential PFC neurochemical innervation by the monoamines, serotonin, dopamine, noradrenaline, and acetylcholine. For example, decreased prefrontal sero - tonin impairs reversal learning, which is a measure of cognitive flexibility requiring adjustment of behavior in the context of previous reward- related occurrences estab- lished that now need to be reversed. Dopamine depletion, on the other hand, impairs set formation. Set formation refers to a tendency to exhibit certain behavioral approaches because past experiences have been favorable. Noradrenaline depletion affects set shift- ing (switching tasks in a non- conscious manner), whereas acetylcholine affects serial reversal learning (SRL). SRL refers to the ability to discriminate between two differently rewarded stimuli in which the reward contingency is then altered by multiple reversals.
When testing animals display fewer errors after repeated reversals with a task, it implies they have behavioral flexibility. These neurotransmitter systems are also involved in so- called state- dependent systems such as attention (dopamine, acetylcholine), arousal (noradrenaline, dopamine), stress (noradrenaline), and affect (serotonin or 5HT), which in turn may amplify/augment these differing executive functions [9]. Executive function as a generic label encompasses the core components of working memory, response inhib- ition, attention, and set shifting or cognitive flexibility. These core components may be altered in various ways to yield the clinical phenotypes of obsessive compulsive disorder (OCD), depression, attention deficit hyperactivity disorder (ADHD), bipolar disorder schizophrenia, and neurodegenerative diseases such as frontotemporal lobe dementias, Alzheimer’s disease, and Parkinson’s disease.
Dopamine
Dopamine is regarded as the principal neurotransmitter within the extensive frontal sub- cortical circuits, discussed in Chapter 5, with dopamine and acetylcholine predominat- ing in the left hemisphere and norepinephrine and 5HT in the right hemisphere. Previc proposed his hypothesis of the dominance of dopamine in the frontal subcortical circuits as a key neurotransmitter critical in heat management as it promoted cooling of our brain and bodies in the thermally stressed condition of the arid East African Rift Valley dur- ing the last 2–3 million years [10]. This allowed superior toleration of hyperthermia and heat stroke and additionally may have enabled early hominoids to use chase hunting to their advantage as the less heat- tolerant herbivores succumbed to overheated muscles or chase myopathy [11,12]. Dopamine presumably became exapted for executive func- tion and regarded as a key neurochemical factor in the human intelligence, becoming the most important neurotransmitter in our brain’s evolution, and fundamental to the core frontal attributes of cognitive flexibility, working memory, abstraction, temporal sequencing, and motor planning [13]. It has also been postulated that further dopamine expansion occurred, on account of upregulated calcium metabolism related to increased
147 The Human Connectome
aerobic activity and an overall increase in tyrosine (dopamine precursor) consequent to increased meat intake [14]. Of clinical relevance today is the pharmacological advisory of dopamine- blocking medications (risperidone, quetiapine, haloperidol) and neuroleptic malignant syndromes or malignant hyperthermia syndrome that may be precipitated.
At a neuronal level, dopamine action affects the signal-to-noise ratio specifically on the PFC pyramidal, glutaminergic cell G- protein linked receptors that are located on the dendritic shafts and spines of glutaminergic pyramidal neurons, as well as acting on the GABA- ergic neuronal dendrites. In this manner, dopamine regulates the critical and core processes of working memory, as well as reasoning and language. All the great apes and humans have the hallmark of dopamine input to all cerebral regions, in contrast to the scarce rodent dopaminergic innervation. There are also regional differences with dopa- minergic distribution, most concentrated in the association cortices within layers 1, 5 and 6 [15]. Humans differ further in that they have a more extensive prefrontal dopaminergic input compared to great apes. These factors together give credence to the dopaminergic evolutionary hypotheses that dopamine, in particular, was a major factor in human cul- ture, tool- making, exploration, and manifold scientific advances [13]. The same capabil- ities, however, have also predisposed humans to the many hyperdopaminergic syndromes that include bipolar disease, autism, schizophrenia, ADHD, and neurodegenerative disease [16].
Acetylcholine
The acetylcholine axons of great apes and humans have varicosities that have been linked to a role in cortical plasticity, mediating self- awareness, social learning, advanced tool- making, and higher- level learning capacity [17]. The five muscarinic G- protein linked receptors (M1–M5) mediate these modulatory effects, whereas the ligand- gated ion channel nicotinic receptors transmit both excitatory and inhibitory effects upon pyramid- al cells and GABA interneurons. The phenotypic cognitive output translates into working memory and cognitive flexibility [18].
Serotonin
Similarly with serotonin innervation, an overall increase of cortical efferent fibers has been noted among the great apes in comparison to other mammals. To date, 14 seroton- ergic G- protein coupled receptors, as well as a single ion channel receptor (5- HT 3) have been described. These modulate a number of different processes that include inhibition, learning, and memory. The serotonin receptors located on pyramidal cells, their den- dritic shafts, and interneurons, enable signal modulation of localized circuits in relation to extrinsic stimuli [19]. An important clinical perspective is that of the serotonergic innervation within the orbitofrontal cortex, which modulates inhibition regulation, emo- tional processing, and self- control [20].
Noradrenaline
Both noradrenaline and dopamine exert critical excitatory innervation for wakefulness, which allows neurons to engage in information processing [21,22]. They also have modu latory effects that augment PFC connections while engaging in working memory oper ations. Both noradrenaline and dopamine display “inverted U- shaped” effects on working memory, with either too much or too little of either neurotransmitter impairing PFC performance. Noradrenaline stimulates different receptors depending on how much
has been released, displaying the highest affinity for α2- adrenergic receptors with lower affinity for beta- adrenergic and α1 receptors [23]. Optimal levels of noradrenaline for alertness without undue stress occur with α2A- receptor stimulation [24,25].
With significant stressors, elevated noradrenaline levels stimulate more of the α1- receptors and β1- receptors, with consequent impairment of PFC activity [26,27]. Both dopamine and noradrenaline release occurs during acute stress, whereas mild stress increases only dopamine release [28]. Depletion of noradrenaline or blocking of PFC α2A- receptors leads to working memory dysfunction, whereas stimulation of α2A- receptors augments working memory function [29]. Alternatively, high levels of PFC α1- receptor stimulation decreases spatial working memory function [30,31]. In the set- ting of cognitive impairment attributed to stress, these can be ameliorated by issuing α1- receptor antagonists. Important clinical consequences include the success demonstrated with using α1- receptor antagonists such as prazosin benefiting those with PTSD [32,33].
Similarly, β- receptor antagonist treatment has also been shown to improve cognitive flex- ibility in association with stress. Dopamine effects on working memory occur through the D1 receptor group (D1 and D5), also with an inverted U- shaped effect with both excessive stimulation or blocking of the D1 receptor family leading to working mem- ory function deterioration [34,35]. D1 blockade by D1 antagonists ameliorates work- ing memory impairment during stress. These findings support complementary roles for noradrenaline and dopamine, with α2A- receptor stimulation enhancing PFC network firing with overall signal increase, and D1 receptor stimulation decreasing firing to non- preferred inputs and so shaping neuronal firing with decreased “noise” [36].
The Mosaic Cognitive Evolution
Primate and hominoid imitation ability and behavior were pivotal to the cultural evo- lution, leading Subiaul to refer to this ability as an “all- purpose learning mechanism.”
Evolution of the imitation circuitry components included anatomical and chemi- cal aspects, as well as reorganization of circuits, the latter termed mosaic circuits. The mosaicism refers to prefrontal cortical, temporal parietal, and cerebellar components.
The major cognitive domains of attention, memory, language, and tool use are all based on mosaic patterns. The mosaic pattern itself was modeled on the imitation behavior circuitry, which has auditory, tactile, and visual dimensions [37]. Both serotonergic and dopaminergic chemical networks and their receptors feature in the OFC inhibitory con- trol mechanisms. However, serotonin depletion and not dopamine have been correlated with impairment of OFC inhibitory control. Studies by Walker et al. in marmosets and monkeys demonstrated the more in- depth differential contributions of these two neu- rotransmitters in inhibitory control. Those animals with OFC serotonin depletion were shown to have stimulus- bound responses to discrimination extinction and conditioned reinforcement tests, indicating that OFC serotonin function may be to prevent potentially competing and task- irrelevant inputs from guiding their responses. Dopamine depletion did not display such behavioral responses [38].