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Sensory thalamus and periaqueductal grey area local field potential signals during bladder filling
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Case Reports / Journal of Clinical Neuroscience 68 (2019) 342–343
Sensory thalamus and periaqueductal grey area local field potential signals during bladder filling Holly A. Roy a,⇑, Tipu Z. Aziz a,b, Alexander L. Green a,b a b
Nuffield Department of Surgical Sciences, John Radcliffe Hospital, Oxford, UK Department of Neurosurgery, Level 3, The West Wing, John Radcliffe Hospital, Oxford, UK
a r t i c l e
i n f o
Article history: Received 30 April 2019 Accepted 8 July 2019
Keywords: Deep brain stimulation Bladder Periaqueductal grey area Sensory thalamus Pain
a b s t r a c t The periaqueductal grey area and sensory thalamus are thought to be important nuclei involved in the supraspinal bladder control network. Deep brain stimulation of the periqueductal grey area has been shown to increase bladder capacity in the human. In a single patient, we have recorded local field potential signals from implanted deep brain stimulation electrodes within the sensory thalamus during filling cystometry with periaqueductal grey area deep brain stimulation in the ON and OFF states. In the OFF stimulation state, we demonstrate correlations between bladder volume and oscillations in the high gamma frequency band in the sensory thalamus. Stimulation of the periaqueductal grey area abolishes this correlated activity in the gamma frequency band and also suppresses oscillations within the sensory thalamus in the alpha frequency band. These findings support the involvement of the sensory thalamus in the afferent limb of bladder-related brain networks. They also suggest that periaqueductal grey area deep brain stimulation may disrupt the normal processing of afferent signals within the sensory thalamus which may be related to the effect of stimulation on bladder capacity. Ó 2019 Elsevier Ltd. All rights reserved.
1. Introduction The periaqueductal gray area (PAG) is a midbrain nucleus, which is used as a therapeutic target for deep brain stimulation (DBS) to treat chronic pain [1]. In addition to its involvement in pain pathways, the PAG has been implicated in a variety of physiological functions, including micturition, and DBS of the human PAG increases maximal bladder capacity, [2]. The sensory thalamus (VPL) is thought to receive afferent signals related to bladder distension [3]. In order to understand the mechanism underlying the effect of PAG stimulation on bladder function, we used implanted depth electrodes to record local field potentials (LFPs) from the PAG and sensory thalamus (VPL) of a human subject during bladder filling with PAG DBS ON and OFF. 2. Case history A 51-year-old man underwent DBS of the left PAG and left VPL for the treatment of medication-refractory right arm phantom limb pain. He had no co-morbidities and was taking no medications at the time of testing. The patient gave informed consent for his participation and the study protocol conformed with the declaration of Helsinki and received local ethical approval. The urodynamic data collected from this subject have been published elsewhere [2].
desire to void, (4) very strong (‘‘desperate”) desire to void, and (5) maximal bladder capacity. The VPL electrode was turned off throughout testing and connected to a portable physiological measuring system (Porti 7, TMSI International) for LFP recording. Two bladder filling cycles were performed with PAG stimulation turned ON (1.0 V, 210 ls, 50 Hz), and two filling cycles were carried out with PAG stimulation turned OFF, in the order OFF/ON/OFF/ON. While the PAG stimulation was turned OFF, PAG LFPs were recorded. Signals were analysed offline using Spike II software (version 7, Cambridge Electronic Design, Cambridge, UK) and the NSPL toolbox in Matlab (Mathworks Inc, MA, USA). A data segment of 10-second duration immediately preceding reported change in bladder sensation was identified, downsampled to 1000 Hz and exported to NSPL. Bipolar signals were low pass filtered at 200 Hz, high pass filtered at 2 Hz, and bandstop filtered at 50 Hz using a Butterworth filter to exclude mains artefact. Power spectral density analysis was performed on the 10 s data segments using a 1.5 s Hanning window and the power in the following frequency bands was measured: 4–8, 8–12, 12–25, 25–60, 60–90, 90– 150 Hz. LFP power in each band was normalised relative to ‘‘rest” for each fill (defined as power during a 10 s segment of initial filling prior to initial bladder sensation.) Statistical analyses were carried out in SPSS (version 20, IBM). Correlational analyses were performed using Pearson’s correlation (two-tailed) and significance at p < 0.05 is reported.
3. Methods The patient underwent DBS surgery for implantation of the PAG and VPL electrodes in a 2-stage procedure as described elsewhere [5]. While the electrodes were externalized and therefore available to record from, the patient underwent 4 cycles of filling cystometry (see [2] for details). The bladder was infused with a sterile solution of isotonic saline at a rate of 24 ml min 1 and the patient asked to indicate when he experienced the following bladder sensations: (1) first sensation of bladder filling (2) initial desire to void (3) strong ⇑ Corresponding author at: Neurosurgery Department, Derriford Hospital, Plymouth, PL6 8DH, UK. E-mail address: [email protected] (H.A. Roy).
4. Results Mean maximal bladder capacity with PAG DBS ON was 201mls and with PAG DBS OFF was 168mls. There was a correlation between PAG and VPL LFP signals in the alpha (8–12 Hz) frequency band (p = 0.003) (Fig. 1). There was also an inverse correlation between bladder volume and VPL LFP power in the high gamma frequency band (90–150 Hz) (p = 0.039) (Fig. 2). However, in the PAG, there was no correlation between bladder volume or intensity of desire to void and LFP power in any frequency band.
Case Reports / Journal of Clinical Neuroscience 68 (2019) 342–343
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power and bladder volume with PAG DBS ON. There was also suppression of normalized alpha power overall during bladder filling with PAG DBS ON relative to OFF (paired samples t-test, p < 0.001). 5. Discussion
Fig. 1. Correlation between alpha power in the PAG and the VPL during bladder filling (DBS OFF).
LFPs are extracellular potentials that reflect the summed excitatory and inhibitory post-synaptic potentials of a local population of neurons, and provide an excellent measure of local neuronal activity. We identified a correlation between activity in the PAG and VPL in the alpha band during bladder filling, indicating neuronal synchronization between the PAG and VPL. We also demonstrated significant inverse correlations between VPL activity in the high gamma band and bladder volume. This suggests that the VPL is involved in processing afferent bladder information, as demonstrated by previous studies of single-unit extracellular potential activity in the monkey VPL in response to urinary bladder distension [3]. We also wanted to understand whether PAG DBS influenced sensory processing of signals in the VPL, as this could provide an explanation for the effect of PAG DBS on bladder capacity in humans. We found that there was no longer a correlation between VPL high gamma power and bladder volume with PAG DBS ON, implying that PAG DBS disrupted neuronal processing of bladder filling information in the VPL.Furthermore, comparing normalized VPL power in the alpha band between DBS OFF and ON states revealed a significant suppression of power with DBS ON, consistent with previous studies [4]. This may represent a possible mechanism by which PAG DBS alleviates pain, including potentially the discomfort associated with a distended bladder. Although the PAG is well established as an important region in the afferent and efferent limbs of the micturition pathway, we did not observe consistent activity within the PAG that correlated linearly with increasing bladder volume. This may imply a more complex relationship between neuronal activity in the PAG and bladder volume and should be the subject of further investigation.
Acknowledgement This work was supported by the Dunhill Medical Trust and the Royal College of Surgeons England.
References Fig. 2. Correlation between 90 and 150 Hz power in the VPL with increasing bladder volume.
The VPL LFP response to bladder filling was compared between the PAG DBS OFF and ON trials. In the 90–150 Hz frequency band there was no longer a significant inverse correlation between LFP https://doi.org/10.1016/j.jocn.2019.07.037
[1] [2] [3] [4] [5]
Reynolds et al. Science 1969;164:444–5. Green et al. Ann Neurol 2012;72:144–7. Chandler et al. Brain Res (571), 26–34. Wu et al. Exp Brain Res 2014;232:527–34. Owen SLF, Green AL, Stein JF, Aziz TZ. Pain 2006;120:202–6.
Case Reports / Journal of Clinical Neuroscience 68 (2019) 342–343
Sensory thalamus and periaqueductal grey area local field potential signals during bladder filling Holly A. Roy a,⇑, Tipu Z. Aziz a,b, Alexander L. Green a,b a b
Nuffield Department of Surgical Sciences, John Radcliffe Hospital, Oxford, UK Department of Neurosurgery, Level 3, The West Wing, John Radcliffe Hospital, Oxford, UK
a r t i c l e
i n f o
Article history: Received 30 April 2019 Accepted 8 July 2019
Keywords: Deep brain stimulation Bladder Periaqueductal grey area Sensory thalamus Pain
a b s t r a c t The periaqueductal grey area and sensory thalamus are thought to be important nuclei involved in the supraspinal bladder control network. Deep brain stimulation of the periqueductal grey area has been shown to increase bladder capacity in the human. In a single patient, we have recorded local field potential signals from implanted deep brain stimulation electrodes within the sensory thalamus during filling cystometry with periaqueductal grey area deep brain stimulation in the ON and OFF states. In the OFF stimulation state, we demonstrate correlations between bladder volume and oscillations in the high gamma frequency band in the sensory thalamus. Stimulation of the periaqueductal grey area abolishes this correlated activity in the gamma frequency band and also suppresses oscillations within the sensory thalamus in the alpha frequency band. These findings support the involvement of the sensory thalamus in the afferent limb of bladder-related brain networks. They also suggest that periaqueductal grey area deep brain stimulation may disrupt the normal processing of afferent signals within the sensory thalamus which may be related to the effect of stimulation on bladder capacity. Ó 2019 Elsevier Ltd. All rights reserved.
1. Introduction The periaqueductal gray area (PAG) is a midbrain nucleus, which is used as a therapeutic target for deep brain stimulation (DBS) to treat chronic pain [1]. In addition to its involvement in pain pathways, the PAG has been implicated in a variety of physiological functions, including micturition, and DBS of the human PAG increases maximal bladder capacity, [2]. The sensory thalamus (VPL) is thought to receive afferent signals related to bladder distension [3]. In order to understand the mechanism underlying the effect of PAG stimulation on bladder function, we used implanted depth electrodes to record local field potentials (LFPs) from the PAG and sensory thalamus (VPL) of a human subject during bladder filling with PAG DBS ON and OFF. 2. Case history A 51-year-old man underwent DBS of the left PAG and left VPL for the treatment of medication-refractory right arm phantom limb pain. He had no co-morbidities and was taking no medications at the time of testing. The patient gave informed consent for his participation and the study protocol conformed with the declaration of Helsinki and received local ethical approval. The urodynamic data collected from this subject have been published elsewhere [2].
desire to void, (4) very strong (‘‘desperate”) desire to void, and (5) maximal bladder capacity. The VPL electrode was turned off throughout testing and connected to a portable physiological measuring system (Porti 7, TMSI International) for LFP recording. Two bladder filling cycles were performed with PAG stimulation turned ON (1.0 V, 210 ls, 50 Hz), and two filling cycles were carried out with PAG stimulation turned OFF, in the order OFF/ON/OFF/ON. While the PAG stimulation was turned OFF, PAG LFPs were recorded. Signals were analysed offline using Spike II software (version 7, Cambridge Electronic Design, Cambridge, UK) and the NSPL toolbox in Matlab (Mathworks Inc, MA, USA). A data segment of 10-second duration immediately preceding reported change in bladder sensation was identified, downsampled to 1000 Hz and exported to NSPL. Bipolar signals were low pass filtered at 200 Hz, high pass filtered at 2 Hz, and bandstop filtered at 50 Hz using a Butterworth filter to exclude mains artefact. Power spectral density analysis was performed on the 10 s data segments using a 1.5 s Hanning window and the power in the following frequency bands was measured: 4–8, 8–12, 12–25, 25–60, 60–90, 90– 150 Hz. LFP power in each band was normalised relative to ‘‘rest” for each fill (defined as power during a 10 s segment of initial filling prior to initial bladder sensation.) Statistical analyses were carried out in SPSS (version 20, IBM). Correlational analyses were performed using Pearson’s correlation (two-tailed) and significance at p < 0.05 is reported.
3. Methods The patient underwent DBS surgery for implantation of the PAG and VPL electrodes in a 2-stage procedure as described elsewhere [5]. While the electrodes were externalized and therefore available to record from, the patient underwent 4 cycles of filling cystometry (see [2] for details). The bladder was infused with a sterile solution of isotonic saline at a rate of 24 ml min 1 and the patient asked to indicate when he experienced the following bladder sensations: (1) first sensation of bladder filling (2) initial desire to void (3) strong ⇑ Corresponding author at: Neurosurgery Department, Derriford Hospital, Plymouth, PL6 8DH, UK. E-mail address: [email protected] (H.A. Roy).
4. Results Mean maximal bladder capacity with PAG DBS ON was 201mls and with PAG DBS OFF was 168mls. There was a correlation between PAG and VPL LFP signals in the alpha (8–12 Hz) frequency band (p = 0.003) (Fig. 1). There was also an inverse correlation between bladder volume and VPL LFP power in the high gamma frequency band (90–150 Hz) (p = 0.039) (Fig. 2). However, in the PAG, there was no correlation between bladder volume or intensity of desire to void and LFP power in any frequency band.
Case Reports / Journal of Clinical Neuroscience 68 (2019) 342–343
343
power and bladder volume with PAG DBS ON. There was also suppression of normalized alpha power overall during bladder filling with PAG DBS ON relative to OFF (paired samples t-test, p < 0.001). 5. Discussion
Fig. 1. Correlation between alpha power in the PAG and the VPL during bladder filling (DBS OFF).
LFPs are extracellular potentials that reflect the summed excitatory and inhibitory post-synaptic potentials of a local population of neurons, and provide an excellent measure of local neuronal activity. We identified a correlation between activity in the PAG and VPL in the alpha band during bladder filling, indicating neuronal synchronization between the PAG and VPL. We also demonstrated significant inverse correlations between VPL activity in the high gamma band and bladder volume. This suggests that the VPL is involved in processing afferent bladder information, as demonstrated by previous studies of single-unit extracellular potential activity in the monkey VPL in response to urinary bladder distension [3]. We also wanted to understand whether PAG DBS influenced sensory processing of signals in the VPL, as this could provide an explanation for the effect of PAG DBS on bladder capacity in humans. We found that there was no longer a correlation between VPL high gamma power and bladder volume with PAG DBS ON, implying that PAG DBS disrupted neuronal processing of bladder filling information in the VPL.Furthermore, comparing normalized VPL power in the alpha band between DBS OFF and ON states revealed a significant suppression of power with DBS ON, consistent with previous studies [4]. This may represent a possible mechanism by which PAG DBS alleviates pain, including potentially the discomfort associated with a distended bladder. Although the PAG is well established as an important region in the afferent and efferent limbs of the micturition pathway, we did not observe consistent activity within the PAG that correlated linearly with increasing bladder volume. This may imply a more complex relationship between neuronal activity in the PAG and bladder volume and should be the subject of further investigation.
Acknowledgement This work was supported by the Dunhill Medical Trust and the Royal College of Surgeons England.
References Fig. 2. Correlation between 90 and 150 Hz power in the VPL with increasing bladder volume.
The VPL LFP response to bladder filling was compared between the PAG DBS OFF and ON trials. In the 90–150 Hz frequency band there was no longer a significant inverse correlation between LFP https://doi.org/10.1016/j.jocn.2019.07.037
[1] [2] [3] [4] [5]
Reynolds et al. Science 1969;164:444–5. Green et al. Ann Neurol 2012;72:144–7. Chandler et al. Brain Res (571), 26–34. Wu et al. Exp Brain Res 2014;232:527–34. Owen SLF, Green AL, Stein JF, Aziz TZ. Pain 2006;120:202–6.