The study of interconnected brain circuits that drive behavior has been greatly advanced through newer methods in brain imagining that have documented abnormalities in neural function and connectivity in psychiatric disorders. The past decade has also witnessed the development of revolutionary new techniques—optogenetics and designer receptors and ligands—that provide unprecedented temporal and spatial control of neural circuits and permit detection of neural activity in real time in awake, behaving animals.
Positron emission tomography (PET), diffusion tensor imaging (DTI), and functional magnetic resonance imaging (fMRI) have identified neural circuits that contribute to psychiatric disorders, for example, defining the neural circuitry of mood within the brain’s limbic system (Fig. 60-2). Integral to this system are the nucleus accumbens (important also for brain reward—see below), amygdala, hippocampus, and regions of prefrontal cortex. Recent optogenetic research in animals, where the activity of specific types of neurons in defined circuits can be controlled with light, has confirmed the importance of this limbic circuitry in controlling depression-related behavioral abnormalities. Given that many symptoms of depression (so-called neurovegetative symptoms) involve physiologic functions, a key role for the hypothalamus is also presumed. A subset of depressed individuals shows a small reduction in hippocampal size, as noted above. In addition, brain imaging investigations have revealed increased activation of the amygdala by negative stimuli and reduced activation of the nucleus accumbens by rewarding stimuli. There is also evidence for altered activity in prefrontal cortex, such as hyperactivity of subgenual area 25 in anterior cingulate cortex. Such findings have led to trials of deep brain stimulation (DBS) of either the nucleus accumbens or subgenual area 25, which appears to be therapeutic in some severely depressed individuals.
Neural circuitry of depression and addiction. The figure shows a simplified summary of a series of limbic circuits in brain that regulate mood and motivation and are implicated in depression and addiction. Shown in the figure are the hippocampus (HP) and amygdala (Amy) in the temporal lobe, regions of prefrontal cortex, nucleus accumbens (NAc), and hypothalamus (Hyp). Only a subset of the known interconnections among these brain regions is shown. Also shown is the innervation of several of these brain regions by monoaminergic neurons. The ventral tegmental area (VTA) provides dopaminergic input to each of the limbic structures. Norepinephrine (from the locus coeruleus [LC]) and serotonin (from the dorsal raphe [DR] and other raphe nuclei) innervate all of the regions shown. In addition, there are strong connections between the hypothalamus and the VTA-NAc pathway. Important peptidergic projections from the hypothalamus include those from the arcuate nucleus that release β-endorphin and melanocortin and from the lateral hypothalamus that release orexin.
In schizophrenia, structural and functional imaging studies have identified a 3% loss of brain volume, most of which is in gray matter. This loss is progressive, and cortical gray matter appears to be particularly affected over time. The temporal lobes, particularly the left superior temporal gyrus, Heschl gyrus, and planum temporale, are often the most severely affected. The rate of loss in these regions as well as in frontal and parietal lobes appears to be greatest early in the course of the disease. Functional imaging studies provide evidence of reduced metabolic (presumably neural) activity in the dorsolateral prefrontal cortex at rest and when performing tests of executive function, including working memory. There is also evidence for impaired structural and task-related functional connectivity, mainly in frontal and temporal lobes.
These neuroimaging findings in schizophrenia have been confirmed in pathologic studies that show enlargement of the ventricular system and reduction of cortical and subcortical gray matter in frontal and temporal lobes and in the limbic system. The reduction in cortical thickness is associated with increased cell packing density and reduced neuropil (defined as axons, dendrites, and glial cell processes) without an apparent change in neuronal cell number. Specific classes of interneurons in prefrontal cortex consistently show reduced expression of the gene encoding the enzyme glutamic acid decarboxylase 1 (GAD1), which synthesizes γ-aminobutyric acid (GABA), the principal inhibitory neurotransmitter in the brain. Neuregulin 1 (NRG1), a member of the epidermal growth factor (EGF) family of growth factors, and its receptor ERBB4, have been implicated in schizophrenia, and they serve important roles in the maturation of GABAergic interneurons in cerebral cortex; loss of NRG1-ERBB4 in mice leads to a reduced neuropil, thus phenocopying a pathologic finding in schizophrenia. These findings are consistent with one working hypothesis of schizophrenia as a developmental neurodegenerative disorder due in part to loss of cortical interneurons in frontal and temporal lobes.
Work in rodent and nonhuman primate models of addiction has established the brain’s reward regions as key neural substrates for the acute actions of drugs of abuse and for addiction induced by repeated drug administration (Fig. 60-2). Midbrain dopamine neurons in the VTA function normally as rheostats of reward: they are activated by natural rewards (food, sex, social interaction) or even by the expectation of such rewards, and many are suppressed by the absence of an expected reward or by aversive stimuli. These neurons thereby transmit crucial survival signals to the rest of the limbic brain to promote reward-related behavior, including motor responses to seek and obtain the rewards (nucleus accumbens), memories of reward-related cues (amygdala, hippocampus), and executive control of obtaining rewards (prefrontal cortex).
Drugs of abuse alter neurotransmission through initial actions at different classes of ion channels, neurotransmitter receptors, or neurotransmitter transporters (Table 60-2). Studies in animal models have demonstrated that although the initial targets differ, the actions of these drugs converge on the brain’s reward circuitry by promoting dopamine neurotransmission in the nucleus accumbens and other limbic targets of the VTA. In addition, some drugs promote activation of opioid and cannabinoid receptors, which modulate this reward circuitry. By these mechanisms, drugs of abuse produce powerful rewarding signals, which, after repeated drug administration, corrupt a vulnerable brain’s reward circuitry in ways that promote addiction. Three major pathologic adaptations have been described. First, drugs produce tolerance and dependence in reward circuits, which promote escalating drug intake and a negative emotional state during drug withdrawal that promotes relapse. Second, sensitization to the rewarding effects of the drugs and associated cues is seen during prolonged abstinence and also triggers relapse. Third, executive function is impaired in such a way as to increase impulsivity and compulsivity, both of which promote relapse.
TABLE 60-2INITIAL ACTIONS OF DRUGS OF ABUSE ||Download (.pdf) TABLE 60-2INITIAL ACTIONS OF DRUGS OF ABUSE
|DRUG ||NEUROTRANSMITTER AFFECTED ||DRUG TARGET (ACTION) |
|Opiates ||Endorphins, enkephalins ||μ- and δ-opioid receptors (agonist) |
|Psychostimulants (cocaine, amphetamine, methamphetamine) ||Dopamine ||Dopamine transporter (antagonist—cocaine; reverse transport—amphetamine, methamphetamine) |
|Nicotine ||Acetylcholine ||Nicotinic cholinergic receptors (agonist) |
|Ethanol ||GABA ||GABAA receptors (positive allosteric modulator) |
|Glutamate ||NMDA glutamate receptors (antagonist) |
|Acetylcholine ||Nicotinic cholinergic receptors (allosteric modulator) |
|Serotonin— ||5HT-3 receptor (positive allosteric modulator) Calcium-activated K+ channel (activator) |
|Marijuana ||Endocannabinoids (anandamide, 2-arachidonoylglycerol) ||CB1 receptor (agonist) |
|Phencyclidine ||Glutamate ||NMDA glutamate receptor (antagonist) |
Imaging studies in humans confirm that addictive drugs, as well as craving for them, activate the brain’s reward circuitry. In addition, patients who abuse alcohol or psychostimulants show reduced gray matter in the prefrontal cortex as well as reduced activity in anterior cingulate and orbitofrontal cortex during tasks of attention and inhibitory control. It is thought that damage to these cortical areas contributes to addiction by impairing decision-making and increasing impulsivity.