Elsevier

Behavioural Brain Research

Volume 224, Issue 1, 10 October 2011, Pages 15-22
Behavioural Brain Research

Research report
Dysfunctional long-term potentiation-like plasticity in schizophrenia revealed by transcranial direct current stimulation

https://doi.org/10.1016/j.bbr.2011.05.017Get rights and content

Abstract

Neural and cortical plasticity represent the ability of the brain to reorganize its function in response to a challenge. Plasticity involves changing synaptic activity and connectivity. Long-term-potentiation is one important mechanism underlying these synaptic changes. Disturbed neuronal plasticity is considered to be part of the pathophysiology of schizophrenia and has been linked to the different clinical features of this severe illness. The aim of the present study was to investigate nonfocal cortical plasticity and cortical excitability in recent-onset and multi-episode schizophrenia compared with healthy subjects. Nonfocal cortical plasticity can be induced in the motor cortex of healthy subjects with anodal transcranial direct current stimulation. Animal and human research indicates that this long-term-potentiation-like plasticity is glutamate-dependent and that these plasticity shifts can last for several hours. Transcranial direct current stimulation-induced plasticity was monitored by transcranial magnetic stimulation-generated motor evoked potentials. Well-characterized transcranial magnetic stimulation protocols were applied to determine the physiological basis of plasticity changes. Multi-episode schizophrenia patients showed significantly reduced long-term-potentiation-like plasticity compared to recent-onset schizophrenia patients and healthy controls. All schizophrenia patients demonstrated reduced cortical inhibition. Our results indicate that the long-term-potentiation-like plasticity deficit in schizophrenia patients is related to the disease course. Disturbances of N-methyl-d-aspartate, gamma-aminobutyric acid and dopamine receptors may account for this plasticity deficit. LTP-like plasticity deficits might be related to disturbed information processing in schizophrenia patients.

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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