Schizophrenia and the disruption to the interface between the emotions and cognition

As mentioned on the previous page the anterior cingulate cortex (ACC) is a relatively recently evolved interface between the emotions and cognition (1) and there is evidence to show that there is dysfunction of this structure in schizophrenics (2, 3) . In other words the link between the modern intellect (cortex) and the ancient paleomammalian brain (limbic system) is disrupted leading to lowered cognitive abilities or diminished intellect in schizophrenics.

Spindle cells (or von Economo neurons [VEN]) are specialised elongated neurons found only in humans and some higher primates. These are located in the ACC and link the cortex over long distances to various areas of the brain including the limbic system and contain receptors for various agents including dopamine, serotonin and DISC1 (disrupted in schizophrenia) which is highly expressed in schizophrenia (4) .

In schizophrenia or psychosis it appears that there are changes in density of the VEN (5, 6) . Reduced density has been found in early onset Schizophrenia (5) with individual cell damage being found in schizophrenia (6) demonstrated by increased lysosome aggregation (7) whereas in psychopathic suicide cases, increased density has been reported (5).

There is evidence especially from imaging that the default mode network (DMN) is disrupted in schizophrenia (8, 9) and also other networks (10) such as the Salience Network and the Executive Control Network (11) . Functional Magnetic Resonance Imaging (fMRI) has shown that there is significantly reduced functional connectivity between the cerebellum and the thalamus and also several frontal regions including the middle frontal gyrus, anterior cingulate cortex, and supplementary motor area in subjects with schizophrenia than controls (8) .

Dopamine and glutamate pathways and interactions

Excess dopamine is thought to be the cause of schizophrenia (12). Evidence for this is revealed by the fact that dopamine receptor blockers control the symptoms of schizophrenia/psychosis (12) . However, glutamate agonists also work (12) as if low levels of glutamate may also be the cause (12) . Also glutamate agonists may also increase dopamine levels (12). It has been postulated that disruption of the glutamate, GABA (gamma-aminobutyric acid), dopamine pathway may be involved (13) and also other neurotransmitter systems implicating faulty interneurons (14) .

 

 

Dopamine, Gamma-aminobutyric acid (GABA) and glutamate reward pathways

 

Disruption of pathways, feedback and networks in schizophrenia leading to weakened links between the cortex and amygdala etc.

The disruption of the pathways shown above and the modulation mechanisms between dopamine, glutamate and GABA (15-17) leads to weakened links between the cortex (hence intellect) other areas of the brain particularly the amygdala (hence emotions, pleasure, violence, pain etc.) (15-17,18, 19). Hence in schizophrenics intellect and control declines and emotions become dominant.

 

References

1. Allman JM, Hakeem A, Erwin JM, et al. The anterior cingulate cortex. The evolution of an interface between emotion and cognition. Ann N Y Acad Sci 2001;935:107-17. [published Online First: 2001/06/20]

2. Adams R, David AS. Patterns of anterior cingulate activation in schizophrenia: a selective review. Neuropsychiatric Disease and Treatment 2007;3(1):87-101.

3. Stevens FL, Hurley RA, Taber KH. Anterior cingulate cortex: unique role in cognition and emotion. The Journal of neuropsychiatry and clinical neurosciences 2011;23(2):121-5. doi: 10.1176/appi.neuropsych.23.2.121 10.1176/jnp.23.2.jnp121 [published Online First: 2011/06/17]

4. Cauda F, Geminiani GC, Vercelli A. Evolutionary appearance of von Economo's neurons in the mammalian cerebral cortex. Front Hum Neurosci 2014;8:104. doi: 10.3389/fnhum.2014.00104 [published Online First: 2014/03/29]

5. Brune M, Schobel A, Karau R, et al. Neuroanatomical correlates of suicide in psychosis: the possible role of von Economo neurons. PLoS One 2011;6(6):e20936. doi: 10.1371/journal.pone.0020936 [published Online First: 2011/07/07]

6. Brune M, Schobel A, Karau R, et al. Von Economo neuron density in the anterior cingulate cortex is reduced in early onset schizophrenia. Acta neuropathologica 2010;119(6):771-8. doi: 10.1007/s00401-010-0673-2 [published Online First: 2010/03/24]

7. Krause M, Theiss C, Brune M. Ultrastructural Alterations of Von Economo Neurons in the Anterior Cingulate Cortex in Schizophrenia. Anatomical record (Hoboken, NJ : 2007) 2017;300(11):2017-24. doi: 10.1002/ar.23635 [published Online First: 2017/07/07]

8. Wang L, Zou F, Shao Y, et al. Disruptive changes of cerebellar functional connectivity with the default mode network in schizophrenia. Schizophr Res 2014;160(1-3):67-72. doi: 10.1016/j.schres.2014.09.034 [published Online First: 2014/12/03]

9. Pomarol-Clotet E, Canales-Rodríguez EJ, Salvador R, et al. Medial prefrontal cortex pathology in schizophrenia as revealed by convergent findings from multimodal imaging. Molecular Psychiatry 2010;15:823. doi: 10.1038/mp.2009.146

https://www.nature.com/articles/mp2009146#supplementary-information

10. Ray KL, Lesh TA, Howell AM, et al. Functional network changes and cognitive control in schizophrenia. NeuroImage Clinical 2017;15:161-70. doi: 10.1016/j.nicl.2017.05.001 [published Online First: 2017/05/23]

11. Seeley WW, Menon V, Schatzberg AF, et al. Dissociable intrinsic connectivity networks for salience processing and executive control. J Neurosci 2007;27(9):2349-56. doi: 10.1523/jneurosci.5587-06.2007 [published Online First: 2007/03/03]

12. Seeman P. Glutamate and dopamine components in schizophrenia. J Psychiatry Neurosci 2009;34(2):143-9. [published Online First: 2009/03/10]

13. Schwartz TL, Sachdeva S, Stahl SM. Glutamate neurocircuitry: theoretical underpinnings in schizophrenia. Frontiers in pharmacology 2012;3:195. doi: 10.3389/fphar.2012.00195 [published Online First: 2012/11/29]

14. Yang AC, Tsai SJ. New Targets for Schizophrenia Treatment beyond the Dopamine Hypothesis. Int J Mol Sci 2017;18(8) doi: 10.3390/ijms18081689 [published Online First: 2017/08/05]

15. Chuhma N, Mingote S, Kalmbach A, et al. Heterogeneity in Dopamine Neuron Synaptic Actions Across the Striatum and Its Relevance for Schizophrenia. Biol Psychiatry 2017;81(1):43-51. doi: 10.1016/j.biopsych.2016.07.002 [published Online First: 2016/10/04]

16. Tomasetti C, Iasevoli F, Buonaguro EF, et al. Treating the Synapse in Major Psychiatric Disorders: The Role of Postsynaptic Density Network in Dopamine-Glutamate Interplay and Psychopharmacologic Drugs Molecular Actions. Int J Mol Sci 2017;18(1) doi: 10.3390/ijms18010135 [published Online First: 2017/01/14]

17. Jauhar S, McCutcheon R, Borgan F, et al. The relationship between cortical glutamate and striatal dopamine in first-episode psychosis: a cross-sectional multimodal PET and magnetic resonance spectroscopy imaging study. The lancet Psychiatry 2018;5(10):816-23. doi: 10.1016/s2215-0366(18)30268-2 [published Online First: 2018/09/22]

18. Benes FM, McSparren J, Bird ED, et al. Deficits in small interneurons in prefrontal and cingulate cortices of schizophrenic and schizoaffective patients. Archives of General Psychiatry 1991;48(11):996-1001. doi: 10.1001/archpsyc.1991.01810350036005

19. Benes FM, Berretta S. GABAergic Interneurons: Implications for Understanding Schizophrenia and Bipolar Disorder. Neuropsychopharmacology 2001;25:1. doi: 10.1016/S0893-133X(01)00225-1