Consciousguess

Apathy: a multidimensional syndrome with cognitive, behavioural and emotional components, is common in PD and other parkinsonian syndromes. Patients with apathy lack motivation and can become devoid of thoughts, lack concern and emotional reactivity, and show no interest, initiative or spontaneous activity.

The basal ganglia are subcortical nuclei consisting of the:

Striatum (which includes the caudate and putamen)

the Substantia Nigra (SN; including the pars compacta (SNc) and the pars reticulata (SNr))

the SubThalamic Nucleus (STN)

Globus Pallidus (GP; comprising the internal segment (GPi) and the external segment (GPe))

The basal ganglia evolved over 560 million years ago, probably to provide a mechanism for selecting one action from several competing responses, and were traditionally considered the ‘habit system’ of the brain, having a role in the “automatic execution of learned motor plans”

The basal ganglia operate through neuronal inhibition, disinhibition and facilitation. Their output nuclei (the GPi and SNr) hold the cortex and superior colliculus under tonic inhibition to prevent inappropriate movements or saccades, and implement phasic release of this inhibitory control to allow movements and saccades to occur.

The main functional subdivisions in the sensorimotor, associative and associative and limbic cortico–striatal circuits. The basal ganglia not only are connected to motor cortical areas but also have connections with a wide range of non-motor areas of the cortex. Therefore, they are well placed to influence — through these connections — motor (part a), cognitive (or associative; part b) and emotional (part c) processing.

Regions implicated in emotion regulation.

The dorsal anterior cingulate (dACC), insula, amygdala and periaqueductal grey (PAG) (shown in red) have been implicated in emotional reactivity.

By contrast, the dorsolateral prefrontal cortex (dlPFC), ventrolateral PFC (vlPFC), supplementary motor area (SMA), pre-SMA and parietal cortex (shown in blue) have been implicated in ‘explicit’ emotion regulation

and the ventral ACC (vACC)–ventromedial PFC (vmPFC; also shown in blue) has been implicated in ‘implicit’ emotion regulation.

successful treatment of depression appears to be conditional upon a concomitant volume increase in the adult hippocampus Second, that electrically stimulating prefrontal regions implicated in associative processing alleviates depression symptoms, Associative processing and the ability to learn associations between previously unrelated items have been attributed primarily to structures of the MTL, particularly the hippocampus, and the parahippocampal cortex, Several recent studies have demonstrated both functional disturbances and volume reduction of the hippocampal formation in depression. Importantly, the severity of depressive symptoms is directly increased by such hippocampal structural disturbances, as well as by a decrease in hippocampal activity.

In recent years, it has been observed that SSRIs have a direct influence on adult neurogenesis, particularly in the dentate gyrus within the hippocampus. Importantly, serotonin has also been shown to have a central role in learning and memory formation, which is widely believed to be mediated by the MTL and to rely on associations. 

There is accumulating evidence to suggest that hippocampal neurogenesis is not merely an epiphenomenon of the chemical effect of SSRIs, but has a causal effect on the success of SSRI treatment: The newly generated neurons seem to have a direct effect on the state of depression, whereby successful antidepressant treatment is conditional upon successful hippocampal neurogenesis. Indeed, blocking hippocampal neurogenesis substantially reduces the efficiency of antidepressants.

associative activations provide the building blocks that enable thought processes to proceed from one topic to another.

Narrow associative thinking, or rumination, refers to associations that surround a narrow focus, Broad associative activations, by contrast, involve more remote associations and, crucially, activate associations that make thought processes advance from one context to another smoothly, thereby minimizing rumination.

The associations that tie items that share the same context consistently activate three main cortical regions: the medial temporal lobe (MTL), the medial partial cortex (MPC) and the medial prefrontal cortex (MPFC). This contextual association network shows a striking overlap with the cortical network termed the ‘default network’.

Contextual associations and mood are linked here directly first by noting recent reports that patients with depression tend to ignore global context. The link to the single-track, narrow mode of thinking in depression is strengthened further by findings showing that the contextual associations network, including the MTL, MPC and MPFC, functions abnormally in these patients. 

Finally, the link between depression and contextual associations might further be supported by recent findings of adult neurogenesis in the MTL in the context of depression treatment.

Converging activations in MPFC.

The same MPFC region that is stimulated by DBS to treat severe depression and where activation is most indicative of successful treatment (a) is strongly active in studies of context-based associative predictions (b). 

c) Anatomical support for the direct and extensive connection between BA 25 and the MPFC region activated by contextual associations has been reported previously; further support comes from using population maps of probabilistic tractography of strongly interconnected MPFC regions. 

d) The same region (MPFC) shows reduced gray matter in patients suffering from depression compared with patients without depression. 

e) The default network shows striking overlap with the same network that mediates contextual associations and predictions (b). Recruiting this MPFC region by cognitive means, as in (b), could regulate inhibition and retrain the natural tendency to engage in broad associative activation, which is compromised in mood disorders.

Circuit Model of Neuronal Changes Relevant to Models of Schizophrenia. Excitatory activity of cortical pyramidal neurons (light blue) is thought to be reduced in schizophrenia, most likely due to NMDA receptor hypofunction. Because of interactions with inhibitory, GABAergic interneurons (green), decreased excitatory input to neurons in the mesencephalon would lead to increased dopamine activity in the striatum and decreased dopamine activity in the cortex (yellow). Abbreviations: DA, dopamine; GABA, g-aminobutyric acid; NMDA, N-methyl-D-aspartic acid. Reprinted with permission from the American Society of Clinical Investigation: Journal of Clinical Investigation, copyright 2009.

Cockburn et al. used a computational model of reinforcement learning couched in basal ganglia anatomy and physiology to suggest that free choice enhances learning from rewards. The idea is that when an option is freely chosen, unexpected rewards cause stronger long-term potentiation (LTP) of ‘go’ (direct) pathway striatal neurons and more long-term depression (LTD) of ‘no-go’ (indirect) pathway neurons, thus promoting stronger propensity to choose the same option in the future, as compared to a similarly unexpected reward obtained for a forced choice. Cockburn et al. further suggested that the enhancement is due to amplification of positive reward prediction error signals conveyed by dopamine neurons in the substantia nigra pars compacta, which modulate corticostriatal learning in a three-factor learning rule.

They also found a significant interaction between the pattern of preferences for freely chosen options and DARPP-32 genotype: participants with one variant of this gene preferred the most highly rewarding (80%) freely chosen options most strongly, with the preference diminishing as reward probability decreased. By contrast, those without this genotype showed strongest preference for the freely chosen option that was associated with intermediate reward probabilities (60%), with this preference diminishing as reward probability increased.

Model simulations showed that this interaction could be the result of a different balance between learning in the ‘go’ as compared to the ‘no-go’ pathway in the two populations.

Cortical Surface Maps Showing Gray Matter Changes Relevant to Psychosis Onset. 

(A) Cortical surface maps showing regions in which converters to psychosis had significantly greater progressive loss of gray matter thickness compared with nonconverters and controls

(B) Cortical surface maps showing regions in which higher levels of unusual thought content at baseline predicted a steeper rate of gray matter thinning among converters

The CNS continually monitors our interior and exterior environments.

Changes in the internal environment (for example, the degree of contraction of visceral muscles, heart rate, levels of metabolites in the internal milieu, and so on) are sensed by the interoceptive system, signalled to sensory regions of the CNS dedicated to body functions and displayed as neural maps of the body (interoceptive maps).

Changes in the external environment are perceived via the exteroceptive senses (smell, taste, touch, hearing and sight) and displayed in dedicated sensory regions as neural maps of the external world (exteroceptive maps)

Changes displayed in neural maps may trigger ‘action programmes’, There are two main types of action programmes: ‘drives’ and ‘emotions’. Drives are aimed at satisfying basic instinctual needs and include hunger, thirst, libido, exploration and play, care of progeny and attachment to mates. Emotions include disgust, fear, anger, sadness, joy, shame, contempt, pride, compassion and admiration, and they are mostly triggered by the perception or recall of exteroceptive stimuli.

The changes in body state resulting from an action programme are in turn sensed by the interoceptive system and mapped in the CNS. Body state changes mapped in interoceptive neural maps may remain non-conscious or may be experienced consciously as ‘feelings’. Feelings are mental experiences that accompany a change in body state.

Interoceptive pathways and nuclei involved in sensing and mapping body states and generating feelings.

Two main pathways convey information from the internal milieu and viscera to the CNS. Information collected in the posterior insula is projected rostrally to the anterior insula, which engages in crosstalk with other cortical areas (such as the orbitofrontal cortex). Some lamina I pathway fibres project to the insula directly (via the thalamus), bypassing the brainstem.

The vagus nerve carries information from the viscera to the NTS, which then projects to the PBN, PAG and hypothalamus. Each of these structures also projects directly to the insular cortex via the thalamus. Extensive crosstalk between the lamina I and vagal pathways permits the formation of integrated maps of body states. The area postrema (AP) directly senses the internal milieu and is intimately connected to the NTS. SC, superior colliculus.

(nucleus tractus solitarius (NTS), parabrachial nucleus (PBN) and periaqueductal grey (PAG))