Research reportDysfunctional long-term potentiation-like plasticity in schizophrenia revealed by transcranial direct current stimulation
Highlights
► Disturbed plasticity is considered to underlie the pathophysiology of schizophrenia. ► Transcranial magnetic stimulation and transcranial direct current stimulation allow the investigation of cortical plasticity to awake humans. ► Schizophrenia patients showed an impaired LTP-like plasticity, which is related to the disease course compared to healthy controls. ► Schizophrenia patients displayed a cortical disinhibition compared to healthy controls. ► Dysfunctional NMDA-receptors and GABA-receptors may account for the plasticity deficits in schizophrenia.
Introduction
Disturbed neuronal plasticity is considered to be part of the pathophysiology of schizophrenia and has been linked to different clinical features of this severe illness [1], [2]. Neural and cortical plasticity represents the ability of the brain to reorganize its function in response to a challenge, to changing environmental inputs or to individual experience [3], [4]. These alterations are associated with changes of synaptic activity and connectivity, increase in dendritic length, changes in spine density and neurogenesis. One important mechanism that underlies synaptic changes and plasticity is long-term-potentiation (LTP) [5], [6].
The concept of disturbed plasticity in schizophrenia patients is provided from different lines of evidence. First, a dysfunction (hypofunction and hyperfunction) of glutamatergic N-methyl-d-Aspartate receptors (NMDAR) and hyperglutamatergic transmission are supposed to be a crucial pathophysiological state in schizophrenia leading to neurotoxicity and disturbed plasticity [7], [8]. Second, brain tissue of schizophrenia patients revealed abnormalities in different activity-dependent genes and in the function of the secretory protease reelin, which have major roles in neurodevelopment and plasticity [9], [10], [11]. Finally, neurophysiological studies have reported in vivo disturbances of cortical plasticity and excitability in schizophrenia patients. One study group presented evidence for a disrupted focal LTP-like plasticity using paired associative stimulation (PAS) and hypothesized that these plasticity deficits may be caused by NMDAR abnormalities in patients [12]. The same group investigated use-dependent plasticity and found reduced motor reorganization and a dysfunctional plasticity response in schizophrenia [13]. Transcranial magnetic stimulation (TMS) studies revealed disturbed cortical inhibitory circuits in schizophrenia patients, which might be linked to a disturbed GABAergic transmission and to altered cortical plasticity [14], [15], [16], [17], [18].
However, none of these neurophysiological studies has explored the impact of schizophrenia, especially with regard to the impact of recurrent psychotic episodes, on nonfocal cortical LTP-like plasticity. This is of particular importance because nonfocal plasticity might be related to cortical signal-to-noise ratio, which is considered to be disturbed in schizophrenia patients. A reduced signal-to-nose ratio of attractor networks might produce some of the cognitive symptoms of schizophrenia and abnormal cortical noise might support the hypothesis of a disturbed “filter-function” in schizophrenia [19], [20], [21]. Imaging studies revealed that the severity and duration of psychosis contribute to the brain volume changes reported in longitudinal studies. It was suggested that brain volume loss could be attributable to the “toxic” effects of the psychotic state of the brain and that morphological abnormalities are more evident in patients who have suffered from multiple episodes of the disease [22], [23], [24], [25].
The objective of the present anodal transcranial direct current stimulation study (tDCS) was to investigate nonfocal LTP-like plasticity in schizophrenia patients with special regard to the duration and severity of psychosis (recent-onset schizophrenia with one single episode (RO-SZ) vs. multi-episode schizophrenia (ME-SZ)). One recent animal study demonstrated in mouse primary motor cortex slices that anodal tDCS induces a long-lasting synaptic potentiation, which is polarity specific and NMDAR dependent [26]. Furthermore, results from human research imply, that tDCS induces long lasting and polarity depended changes in cortical excitability and focal LTP-like plasticity in healthy awake humans, which are NMDAR dependent [27], [28], [29], [30]. After a sufficiently long stimulation period (10–30 min) long lasting after and LTP-like effects (up to several hours) have been achieved [26], [31], [32].
It was hypothesized that patients with schizophrenia would present altered LTP-like plasticity compared to healthy subjects and that these alterations would be related to the disease course. To determine the physiological basis of these plasticity alterations more specifically, we applied various TMS protocols indicative for well-characterized inhibitory and excitatory neuronal circuits. We hypothesized that schizophrenia patients would display a cortical disinhibition compared to healthy subjects and that this cortical disinhibition may be linked to disturbed LTP-like plasticity.
Section snippets
Participants
A total of 44 individuals were included in this study. 22 in- and outpatients with paranoid schizophrenia from the University Hospital Goettingen were compared with 22 matched healthy subjects with no family history of schizophrenia, recruited from the same geographical area. Subjects with a history of dermatological diseases, dementia, neurological illnesses, substance use disorder, severe brain injuries or brain tumors were excluded from the study.
A consensus diagnosis according to the ICD 10
Sociodemographic and clinical characteristics
All groups were matched according to gender, handedness and smoking status. Both groups were matched according to age, but after separating the schizophrenia group into two groups, the one-way-ANOVA revealed significant difference of age (Healthy controls: 29.95 years ± 6.4; RO-SZ: 29.33 years ± 7.8; ME-SZ: 36.00 years ± 8.0, p = 0.041). Healthy controls and RO-SZ did not differ in age (p = 0.82), but there was a significant age difference between healthy controls and ME-SZ (p = 0.019) and a trendwise
Discussion
The results of this study demonstrate that schizophrenia patients with multiple psychotic episodes (ME-SZ) display a significant deficient LTP-like plasticity as reflected by a reduced MEP-increase after anodal tDCS compared to healthy subjects and to recent-onset schizophrenia (RO-SZ) patients. Healthy subjects and RO-SZ did not differ in LTP-like plasticity. There was also a significant cortical disinhibition (reduced SICI) in all schizophrenia patients compared to healthy controls and anodal
Conclusions
Our finding of a disturbed LTP-like plasticity may have an impact for the design of clinical trials. To date different clinical trials are using plasticity—enhancing techniques (rTMS, theta-burst-stimulation, anodal tDCS) for the treatment of positive (e.g. auditory hallucinations) and negative symptoms of schizophrenia. It should be noticed that observed plasticity—enhancing effect of these techniques in healthy, unmedicated subjects cannot simply be translated to schizophrenia patients.
In
Disclosure
A.H. has been invited to scientific congresses by Astra Zeneca, Lundbeck and Janssen Cilag.
M.A.N. reports no financial relationships with commercial interests.
M.H. reports no financial relationships with commercial interests.
T.S-A. reports no financial relationships with commercial interests.
B.G. reports no financial relationships with commercial interests.
O.G. was honorary speaker for the following companies: Astra Zeneca, Bristol Myers Squibb, Janssen Cilag, Otsuka. O.G. has been invited to
Acknowledgments
Alkomiet Hasan is supported by the Deutsche Forschungsgemeinschaft (DFG grant HA 6091/1-1). Michael A Nitsche is supported by the Deutsche Forschungsgemeinschaft (DFG grant NI 683/6-1). Peter Falkai and Thomas Wobrock are supported by the Deutsche Forschungsgemeinschaft (DFG grant FA 241/10-1).
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Visual cortical plasticity and the risk for psychosis: An interim analysis of the North American Prodrome Longitudinal Study
2021, Schizophrenia ResearchCitation Excerpt :There is limited evidence suggesting impaired input-specific plasticity in a small sample of chronic schizophrenia patients compared to controls using an auditory HFS task (Mears and Spencer, 2012), but we recently found evidence for a normal input-specific plasticity effect in chronic patients using the same visual paradigm employed in the present study (Wynn et al., 2019). While deficits in plasticity in schizophrenia may depend on as yet poorly understood variations in plasticity paradigms and sample characteristics, there is additional evidence for deficient LTP-like neuroplasticity in schizophrenia using somewhat more established motor plasticity paradigms such as transcranial magnetic stimulation (TMS) (Mehta et al., 2019) and direct current stimulation (Hasan et al., 2011). In any case, the impact of deficient LTP may be most evident during the pathogenesis of schizophrenia in late adolescence/early adulthood.
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These authors contributed equally to this work.