The connectomics of treatment resistance
Widespread dysfunction throughout the entire neural network that involves both cortical and subcortical regions is pronounced in TRS and may have an underlying circuit biology that is unique to this most severe form of the illness. Anatomical regions and neural circuits that have been examined comparing those individuals with treatment resistant vs. treatment responsive disease have uncovered more severe pathological findings in all cortical tissues that have been measured. A number of imaging studies using a variety of structural and fMRI methods have examined TRS to elucidate the difference between the phenotypic subtypes of responsive and non-responsive illness. For detailed reviews see Mouchlianitis et al. (51) and Nakajima et al. (52).
The loss of neuronal elements that underlie the symptoms of both TRS and ultra-resistant schizophrenia (clozapine-resistant psychosis) may be more substantial than what is found in those patient phenotypes who have responded to antipsychotic treatment (51, 52). Volumetric, DTI and fMRI studies that have examined intra-regional brain morphology (53–56) inter-regional WM circuit integrity (43, 57–59), and functional connectivity (60–63) specific to TRS have consistently identified a disruption to frontal and temporal lobe regions and the major fiber bundles that connect them.
Studies that have specifically compared patients with treatment responsive schizophrenia vs. TRS have reported greater global volumetric reductions of GM in treatment resistant and ultra-resistant patients. There have been consistent reports of reduced GM volumes predominantly within the dorsolateral prefrontal cortex (DLPFC) (53–56), as well as posterior cortical regions, such as the temporal cortex (53–56), parietal cortex (53, 56) and also within the occipital cortex (53, 55, 56) in TRS. Abnormalities in all regions of the corpus callosum as well as commissural and association long axonal fiber pathways connecting prefrontal, temporal, parietal and occipital regions have also been found, with reduced axonal integrity and more severe structural damage in both chronic illness and treatment-resistant populations (43, 57–59, 64). This evidence seems to suggest that on the spectrum of cellular and circuit disruption characteristic of schizophrenia in general, TRS may involve a more severe type of multi-dysconnectivity of brain networks that spans across almost every region of the brain.
The reduction in cortical GM and WM volumes and distinct WM tract disturbances in TRS may be a consequence of disrupted macro-scale neural architecture and network dysconnectivity that originate within distinct micro-scale neuronal ensembles. Morphometric studies that have been investigated in schizophrenia suggest that cortical volume loss is not related to the reduction of the number of neurons in the cortex, but to architectural neuronal disorganization, reduction in neuronal size, and diminished neuropil (axons, dendrites, and synaptic terminals) (65, 66). The etiology behind the loss of dendritic spines and dendritic length of cortical pyramidal neurons is not entirely clear but may originate from hypofunctioning NMDA glutamate receptors on pyramidal cells and interneurons (67–69). From a circuit perspective, hypofunction of NMDA receptors on GABAergic inhibitory interneurons disinhibits associated pyramidal neurons in the circuit and causes a potentially pathological glutamatergic excitatory effect (70, 71).
Hyperglutamatergia may be a distinct feature of TRS and be differentiated from treatment-responsive disease since greater abnormalities in glutamate function have been found in those patients with TRS while maintaining a relatively normal and intact dopamine function. Neuroimaging measures using fluorine-18-L-dihydroxyphenylalanine (18F-DOPA) as a PET radiotracer found a higher level of striatal dopamine synthesis capacity in patients with schizophrenia who responded to treatment vs. those patients with TRS who had equivalent striatal dopamine levels found in healthy controls (72). The same group later utilized proton magnetic resonance spectroscopy (1H-MRS) imaging in TRS to examine glutamate changes that may be specific to antipsychotic treatment-resistance (73). This was the first group to report high glutamate and glutamine levels in the anterior cingulate cortex (ACC) in TRS as compared to those with schizophrenia in remission, and another group has since replicated this finding (74).
Increased concentrations of glutamate found in the ACC that are specific to TRS are consistent with both the glutamate hyperfunction and the NMDA receptor hypofunction hypotheses of schizophrenia. Normally, glutamate is responsible for regulating inhibitory tone in the brain by binding to NMDA receptors on GABAergic interneurons. The structural mechanism that may cause NMDA receptor hypofunction in TRS can lead to disinhibition of pyramidal neurons and excitatory pathways by the understimulation of inhibitory GABA interneurons (75). The downstream effect can then cause an increase in glutamate release from presynaptic pyramidal neurons and binding to α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and kainate receptors and may be a compensatory effect of the NMDA blockade (75–78). The hyperglutamatergic state can initiate calcium influx and cellular toxicity which, over time, can be detrimental to neuronal networks (79). In treatment-resistant disease, excitatory inputs from pyramidal neurons within the ACC circuit could also be disinhibited, leading to increased glutamate efflux and generating symptoms that fail to respond to D2-blocking medications. Glutamate-mediated excitotoxicity may be responsible for the widespread brain abnormalities and severity of symptoms that are found in TRS.
Disturbances in the functional activity of neural circuits have consistently been reported in TRS. Functional MRI studies that have examined changes in neurophysiological measures also may indicate disordered firing and pathological oscillatory activity that may be more pronounced in TRS (63). Persistent auditory hallucinations are a core feature of psychosis. Poor control of this symptom within the positive symptom domain that persists despite adequate trials of antipsychotic medications is often the clearest and most common indicator of severe treatment resistance. Patients with specific TRS-positive symptom domain phenotypes and experiencing auditory verbal hallucinations (AVH) have been investigated in fMRI studies (60–63).
Functional MRI using magnetically labeled blood water protons as an endogenous tracer (arterial spin labeling) to measure tissue perfusion found increased cerebral blood flow in the left superior temporal gyrus, right supramarginal gyrus, and temporal polar cortex in patients with treatment-resistant AVH (63). Functional resting-state MRI studies that investigated connectivity alterations in the default network in patients with chronic non-responsive AVH and treated patients without AVH found that treatment-resistant patients had increased functional connectivity between the dorsomedial prefrontal cortex and other frontotemporal regions, but reduced connectivity between the ventromedial prefrontal cortex and areas of the cingulate cortex (60). Reduced functional connectivity between the left temporo-parietal junction (TPJ) and right Broca's area and ACC and temporo-cingulate pathways have also been implicated in patients with persistent AVH (61, 62). All functional alterations found were greater in those patients with persistent treatment-resistant symptoms, indicating there may be fundamental differences within these brain network properties that are also specific to TRS.
Network-based statistics can be applied to fMRI data to investigate brain networks and to better delineate the differences in the connectome unique to TRS. Although there have been a number of network-based studies in schizophrenia (31, 32, 45–47), Ganella et al. were the first to measure the connectivity and global and local efficiency of whole-brain functional networks from resting state fMRI data in individuals with TRS compared to healthy controls (80). Whole-brain connectivity analysis in this study showed reductions in functional connectivity between all of the brain lobes, with the majority of reduced connections between fronto-temporal, fronto-occipital, temporo-occipital and temporo-temporal subregions. The majority of reduced functional connections in TRS were found in the temporal lobe (between Heschl's gyrus and the frontal lobe), the occipital lobe (between the cuneus and the frontal lobe), and the frontal lobe (between the paracentral lobule and the occipital lobe). Treatment-resistant individuals showed reduced functional connectivity in the temporal lobes as regions most implicated. Decreased connectivity between frontal and temporal brain hubs regions is a particularly vulnerable circuit consistently reported in several studies in schizophrenia and is also characteristic of the circuit pathophysiology of TRS (80).
In terms of network-based analysis, global network efficiency was significantly reduced in the TRS group compared to controls with significant increases in local efficiency. Reduced global network efficiency indicates that the reduction of functional connectivity and integration between different brain hubs in TRS as a result of the disease process may create surrogate or back-up connections locally (increase in local efficiency) as a homeostatic mechanism and an attempt to compensate for the reduction in longer-range connectivity and restore integration (46, 80).