The Pathophysiological Underpinnings of Gamma-Band Alterations in Psychiatric Disorders

Abstract

Investigating the biophysiological substrates of psychiatric illnesses is of great interest to our understanding of disorders' etiology, the identification of reliable biomarkers, and potential new therapeutic avenues. Schizophrenia represents a consolidated model of γ alterations arising from the aberrant activity of parvalbumin-positive GABAergic interneurons, whose dysfunction is associated with perineuronal net impairment and neuroinflammation. This model of pathogenesis is supported by molecular, cellular, and functional evidence. Proof for alterations of γ oscillations and their underlying mechanisms has also been reported in bipolar disorder and represents an emerging topic for major depressive disorder. Although evidence from animal models needs to be further elucidated in humans, the pathophysiology of γ-band alteration represents a common denominator for different neuropsychiatric disorders. The purpose of this narrative review is to outline a framework of converging results in psychiatric conditions characterized by γ abnormality, from neurochemical dysfunction to alterations in brain rhythms.

Keywords: bipolar disorder; gamma-band oscillations; major depressive disorder; parvalbumin-positive interneurons; perineuronal nets; schizophrenia.

Figure 1

Schematic representation of the interaction between GABAergic PV+ interneurons and pyramidal neurons. Pyramidal neurons send excitatory (+) glutamate-mediated inputs to fast-spiking PV+ interneurons, which in turn send inhibitory (−) feedback signals back to the pyramidal cells. Activated interneurons can propagate inhibitory long-range signals to multiple pyramidal cells and synchronize their activity (E-I balance). PV+ = parvalbumin-positive, E = excitatory, I = inhibitory, PNN = perineuronal net. Created in BioRender.com.

Figure 2

Overview of the outlined pathophysiological cascade in ScZ (left panel) with relevant sample evidence (right panel). (a) Representative photomicrographs showing reduced density of PNNs in the PFC of patients with ScZ as compared to HC (Reprinted from [130] with permission from Elsevier); (b) Scatterplots showing lower cortical density of PV+ interneurons in the DLPFC of SCZ patients vs. HC (horizontal lines indicate mean values) (Reprinted from [196] with permission from Elsevier); (c) γ rhythms abnormalities during WM tasks in ScZ patients vs. HC: grand average event-related oscillations in HC (left upper panel) and ScZ patients (right upper panel) during N-back tasks with varying WM demands (easy/hard), with T = 0 ms representing the stimulus onset (Reprinted from [197] with permission from Elsevier); (d) Intertrial coherence time/frequency analyses: 40-Hz phase-locking deficits in ScZ patients (lower panel) relative to HC (upper panel) (Reprinted from [198] with permission from Elsevier); (e) Decreased coherence in higher frequency ranges (β and γ) between central and frontal areas in ScZ patients vs. HC (Reprinted from [199] with permission from Elsevier); (f) Gamma-power difference maps between resting state and cognitive task in HCs and ScZ patients (Reprinted from [188] (licensed under CCBY 4.0, https://creativecommons.org/licenses/by/4.0/, accessed on 7 December 2023)); (g) Reduced frontal inhibition in ScZ patients compared to HCs following DLPFC stimulation (Reprinted from [200] (licensed under CCBY 4.0, https://creativecommons.org/licenses/by/4.0/, accessed on 7 December 2023)). PNN = Perineuronal Net; PFC = Prefrontal Cortex; HC = Healthy Controls; PV+ = Parvalbumin-positive; DLPFC = Dorsolateral Prefrontal Cortex; WM = Working Memory; EEG = Electroencephalography; DMN = Default Mode Network; TMS = Transcranial Magnetic Stimulation; ERSP = Event-Related Spectral Perturbation.

Figure 3

Overview of the outlined pathophysiological cascade in BD (left panel) with relevant sample evidence (right panel). (a) Decrease in PV+ neurons/PNNs number and density in the TRN of patients with BD as compared to HC (* indicate significance) (Reprinted from [218] (licensed under CCBY 4.0, https://creativecommons.org/licenses/by/4.0/, accessed on 7 December 2023); (b,1) Panoramic confocal microphotograph showing PNNs (blue) surrounding PV+ somata (red) in the deep layers of the DLPFC in HC vs. BD patients (white arrowheads: PV+ somata surrounded by PNNs, yellow arrowheads: PV+ cells lacking PNNs, white arrows: PNNs surrounding PV+ somata); (b,2) Histograms of significant differences in the density of PNNs in HC vs. BD patients (as well as SCZ and MDD) (* indicates significance) (Reprinted from [219] (licensed under CCBY 4.0, https://creativecommons.org/licenses/by/4.0/, accessed on 7 December 2023); (c) Group averaged time-frequency maps of ASSR power for each hemisphere, with color scales signifying ASSR power, showing BD patients’ reduced mean ASSR power and PLF to 40- and 80- Hz stimulation (Reprinted from [256] (licensed under CCBY 4.0, https://creativecommons.org/licenses/by/4.0/, accessed on 7 December 2023)); (d) Lower post-stimulus EEG coherence between F4 and T6 locations in BD patients (red line) as compared to HC (blue line) (Reprinted from [252] with permission from Elsevier); (e) Representative data from an HC and a BD patient: average EEG responses to TMS (grey traces represent the 60 recording channels) for the channel closest to the stimulation site (black trace) over the premotor area; color-coded: ERSP plots reflecting the significant TMS-related changes in amplitude and their duration (Reprinted from [263] with permission from Cambridge University Press). PV+ = Parvalbumin-positive; PNN = Perineuronal Net; TRN = Thalamic Reticular Nucleus; BPD = Bipolar Disorder; SCZ = Schizophrenia; HC = Healthy Controls; DLPFC = Dorsolateral Prefrontal Cortex; SCZ = Schizophrenia; ASSR = Auditory Steady-State Response; PLF = Phase-Locking Factor; EEG = Electroencephalography; TMS = Transcranial Magnetic Stimulation; ERSP = Event-Related Spectral Perturbation.

Figure 4

Overview of the outlined pathophysiological cascade in MDD (left panel) with relevant sample evidence (right panel). (a) Representative images of immunofluorescence staining of PNNs and quantification of neurons (neuronal marker: NeuN+) in the PrL of HC compared to vulnerable and resilient rats in response to CUMS (Reprinted from [284] (licensed under CCBY 4.0, https://creativecommons.org/licenses/by/4.0/, accessed on 7 December 2023); (b) Decreased number of PV+ cells in coronal sections of the cingulate cortex, amygdala and hippocampus in HC vs. refractory depressed rats (Reprinted from [300] (licensed under CCBY 4.0, https://creativecommons.org/licenses/by/4.0/, accessed on 7 December 2023); (c) Graph for modulation of γ oscillatory power calculated as ERS/ERD% (with data pooled across O1 and O2 electrodes): positive values reflect ERS, negative values reflect ERD. Gamma ERS/ERD% during the Sternberg task was lower for MDD patients (orange) compared to HC (blue) (Reprinted from [316] with permission from Elsevier)); (d) Hyperactive frontolimbic and frontocentral resting-state γ connectivity in MDD: γ-band functional connectivity network differences when comparing MDD patients to HC at rest: top 11 most connected brain regions with node sizes representing the number of connections within the network (upper left), grand average of γ functional connectivity strengths within the identified network across MDD patients and HC, respectively (bottom right) (Reprinted from [327] with permission from Elsevier); (e) Increased γ power in MDD patients following rTMS: (e,1) Resting γ power: bar graphs showing mean resting γ power before and after rTMS at the F3 and F4 electrode sites across MDD patients (* indicates significance); (e,2) EEG topographical plots of resting-state γ power; from right to left, the topoplots depict the γ power distribution pre-rTMS, post-rTMS, the difference between pre- and post-rTMS, and the t-value map corresponding to the difference between pre- and post-rTMS; (e,3,4) Scatter plots showing positive correlation between the resting γ power increase at the F3 electrode site and improvements in HAM-D17 and BDI (Reprinted from [324] with permission from Elsevier). PNN = Perineuronal Net; HC = Healthy Controls; PrL = Prelimbic cortex; CUMS = Chronic Unpredictable Mild Stress; PV+ = Parvalbumin-positive; ERS = Event-Related Synchronization; ERD = Event-Related Desynchronization; ERS/ERD% = Event-Related Synchronization/Desynchronization Percentage; MDD = Major Depressive Disorder; rTMS = repetitive Transcranial Magnetic Stimulation; EEG = Electroencephalography; HAM-D17 = Hamilton Depression Rating Scale-17; BDI = Beck Depression Inventory.