Table 1.

Neuroprogressive Alterations across Illness Stages.

Domain	High Risk	First Episode	Early Course	Chronicity
Cognition	SZ- Attenuated or selective deficits relative to chronic patients [5–8] BD- no evidence of premorbid deficits; relatives show verbal memory and executive function deficits [9–14]	Cognitive impairment in SZ and BD [9,11,15–19] Some reports of widespread impairment, others of more selective impairments [20]	Mixed findings: some estimate no additional decline during the early course [21–23]; some show continued decline [24,25], and some show improvement in some areas [23]	Widespread deficits: BD- ~1 SD below the mean [26–28]; SZ- ~2 SD below the mean [3,11,29–31] May be associated with relapse or symptom severity [25,32,33] but findings mixed [22,26]
Structural	GM reductions in middle frontal, prefrontal, superior temporal, ACC, thalamus, hippocampus, parahippocampus [5,34,35] Longitudinal: volume reductions, thinning, SA contraction in whole brain, frontal, superior temporal, fusiform and insula, ACC, precuneus, parahippocampus, ventricular enlargement [36–43] Converters vs Non: reduced insula, ACC, callosum, temporal lobe; increased gyrification [5,40,41,44–47]	Reductions in whole brain, superior temporal, medial frontal, prefrontal and ACC cortices, cerebellum, insula, amygdala, caudate, and ventricular enlargement [5,34,35,48–58] Hippocampal reductions may be comparable to chronic patients [34,52,59–61] Longitudinal: Progressive reductions in cortical SA, whole brain, frontal, temporal, parietal, limbic regions over short time (~2 years) [62]	Frontal, temporal and parietal GM, thalamic volume loss [62,63], most pronounced in the first 2 years after baseline [62] Reduced volume and thickness in multiple regions, which was associated with age [64] Associated with cognitive impairment but only weakly with clinical measures [62]	Significant, widespread GM reductions, including whole brain volume, medial and superior temporal, inferior parietal, frontal, occipital, ACC, hippocampus, parahippocampus, amygdala, insula, thalamus, and cerebellum and ventricular enlargement [34,45,48,49,58–60,65–75] Longitudinal: progressive volume loss into chronicity; greatest annual reduction in superior temporal regions [67]
Connectivity	Reduced in salience, control, auditory and motor networks [76,77]	Mixed findings: Reduced in frontal lobes [78]; abnormalities in DMN and Control Networks [78–80] No difference from HC [81] Improved over 1 year with clinical improvement [82]		More pronounced and extended frontal, temporal and sensorimotor abnormalities [78,81] BD and SZ show similar within network reductions in DMN, Control and Visual networks [83]
White Matter	Mixed: increased in regions of the frontal lobes; decreased in medial temporal and superior parietal, corpus callosum [51,84,85] Longitudinal: reduced in fronto-occipatal fasiculus and cerebellar-thalamic regions during transition [85,86]	Reduced FA in corpus callosum, internal capsule, external capsule, fornix, superior, temporal, inferior fronto-occipital fasciculus, cingulum, uncinate fasciculus; widespread increased diffusivity [87–89] Abnormalities in thalamo-cortical WM connectivity [90]	Frontal and temporal WM volume reductions [62] WM reductions, which were associated with age [64,91]	Widespread prefrontal and frontal, temporal, internal capsule WM reductions [87,91,92] BD and SZ show abnormalities unrelated to age or DOI) [93]

SZ: Schizophrenia; BD: Bipolar Disorder; SD: standard deviation; GM: gray matter; ACC: anterior cingulate cortex; SA: surface area; DMN: Default mode network; HC: healthy control; WM: white matter; DOI: duration of illness.