Since the senior author's (J.E.A.) first report in 1972 of the use of deep brain stimulation (DBS) to control chronic pain, electrodes for DBS have been implanted in 141 patients. Of reported series, this one has the largest number of patients and the longest period of follow-up. The mean age of patients in this study was 51.2 years. The mean length of follow-up was 80 months. Patients had experienced pain for a mean period of 65 months before DBS was attempted; all patients had exhausted other medical and surgical therapies. For the purposes of this study, pain states were characterized as being either nociceptive or deafferentation in nature. Nociceptive pain was treated primarily by stimulation of the periaqueductal or periventricular gray, and deafferentation pain was treated primarily by stimulation of the sensory thalamus. Eighty-four patients were treated for deafferentation pain, which included the thalamic pain syndrome (25 cases), peripheral neuropathic pain (16 cases), anesthesia dolorosa (12 cases), paraplegia pain (11 cases), postcordotomy dyesthesia (5 cases), phantom limb pain (5 cases), thoracic neuralgia (4 cases), and miscellaneous pain states (6 cases). We treated 57 patients with nociceptive pain states, 51 for low back and skeletal pain and 6 for pain from the invasion of cancer. Initial relief of pain was obtained by 83 patients (59%). After the mean follow-up period of 80 months, 42 patients (31%) continued to obtain significant pain relief with DBS. Some pain states, particularly anesthesia dolorosa and paraplegia pain, did not seem to respond to DBS. Major complications of therapy included wound infection (12%) and intracranial hemorrhage (3.5%); there was one death in the series (0.7%).(ABSTRACT TRUNCATED AT 250 WORDS)

Treatment of Chronic Pain by Deep Brain Stimulation: Long Term Follow-up and Review of the Literature

Periaqueductal Gray and Rostromedial Tegmental Inhibitory Afferents to VTA Have Distinct Synaptic Plasticity and Opiate Sensitivity

The lateral habenula (LHb) and the ventral tegmental area (VTA), which form interconnected circuits, have important roles in the crucial control of sensory and cognitive motifs. Signaling in the LHb-VTA pathway can be exacerbated during pain conditions by a hyperactivity of LHb glutamatergic neurons to inhibit local VTA DAergic cells. However, it is still unclear whether and how this circuit is endogenously engaged in pain-related cognitive dysfunctions. To answer this question, we modulated this pathway by expressing halorhodopsin in LHb neurons of adult male rats, and then selectively inhibited the axonal projections from these neurons to the VTA during a working memory (WM) task. Behavioral performance was assessed after the onset of an inflammatory pain model. We evaluated the impact of the inflammatory pain in the VTA synapses by performing immunohistochemical characterization of specific markers for GABAergic (GAD65/67) and dopaminergic neurons (dopamine transporter (DAT), dopamine D2 receptor (D2r) and tyrosine hydroxylase (TH)). Our results revealed that inhibition of LHb terminals in the VTA during the WM delay-period elicits a partial recovery of the performance of pain animals (in higher complexity challenges); this performance was not accompanied by a reduction of nociceptive responses. Finally, we found evidence that the pain-affected animals exhibit VTA structural changes, namely with an upregulation of GAD65/67, and a downregulation of DAT and D2r. These results demonstrate a role of LHb neurons and highlight their responsibility in the stability of the local VTA network, which regulates signaling in frontal areas necessary to support WM processes.

https://www.mdpi.com/2227-9059/11/3/820/pdf?version=1678259858

Role of Glutamatergic Projections from Lateral Habenula to Ventral Tegmental Area in Inflammatory Pain-Related Spatial Working Memory Deficits

Quantitative electroencephalography from freely moving rats is commonly used as a translational tool for predicting drug-effects in humans. We hypothesized that drug-effects may be expressed differently depending on whether the rat is in active locomotion or sitting still during recording sessions, and proposed automatic state-detection as a viable tool for estimating drug-effects free of hypo-/hyperlocomotion-induced effects. We aimed at developing a fully automatic and validated method for detecting two behavioural states: active and inactive, in one-second intervals and to use the method for evaluating ketamine, DOI, d-cycloserine, d-amphetamine, and diazepam effects specifically within each state. The developed state-detector attained high precision with more than 90% of the detected time correctly classified, and multiple differences between the two detected states were discovered. Ketamine-induced delta activity was found specifically related to locomotion. Ketamine and DOI suppressed theta and beta oscillations exclusively during inactivity. Characteristic gamma and high-frequency oscillations (HFO) enhancements of the NMDAR and 5HT2A modulators, speculated associated with locomotion, were profound and often largest during the inactive state. State-specific analyses, theoretically eliminating biases from altered occurrence of locomotion, revealed only few effects of d-amphetamine and diazepam. Overall, drug-effects were most abundant in the inactive state. In conclusion, this new validated and automatic locomotion state-detection method enables fast and reliable state-specific analysis facilitating discovery of state-dependent drug-effects and control for altered occurrence of locomotion. This may ultimately lead to better cross-species translation of electrophysiological effects of pharmacological modulations.

/pdf/pharmaco-electroencephalographic-responses-in-the-rat-differ-38jb2fci5g.pdf

Pharmaco-electroencephalographic responses in the rat differ between active and inactive locomotor states.

There is increasing recognition of the involvement of the nigrostriatal and mesolimbic dopamine systems in the modulation of chronic pain. The first part of the present article reviews the evidence indicating that dopamine exerts analgesic effects during persistent pain by stimulating the D2 receptors in the dorsal striatum and nucleus accumbens (NAc). Thereby, dopamine inhibits striatal output via the D2 receptor-expressing medium spiny neurons (D2-MSN). Dopaminergic neurotransmission in the mesostriatal pathways is hampered in chronic pain states and this alteration maintains and exacerbates pain. The second part of this article focuses on the glutamatergic inputs from the medial prefrontal cortex to the NAc, their activity changes in chronic pain, and their role in pain modulation. Finally, interactions between dopaminergic and glutamatergic inputs to the D2-MSN are considered in the context of persistent pain. Studies using novel techniques indicate that pain is regulated oppositely by two independent dopaminergic circuits linking separate parts of the ventral tegmental area and of the NAc, which also interact with distinct regions of the medial prefrontal cortex.

The Role of Mesostriatal Dopamine System and Corticostriatal Glutamatergic Transmission in Chronic Pain

Deep brain stimulation has been found to be effective in relieving intractable pain. The ventral tegmental area (VTA) plays a role not only in the reward process, but also in the modulation of nociception. Lesions of VTA result in increased pain thresholds and exacerbate pain in several pain models. It is hypothesized that direct activation of VTA will reduce pain experience. In this study, we investigated the effect of direct electrical stimulation of the VTA on mechanical, thermal and carrageenan-induced chemical nociceptive thresholds in Sprague–Dawley rats using our custom-designed wireless stimulator. We found that: (1) VTA stimulation itself did not show any change in mechanical or thermal threshold; and (2) the decreased mechanical and thermal thresholds induced by carrageenan injection in the hind paw contralateral to the stimulation site were significantly reversed by VTA stimulation. To further explore the underlying mechanism of VTA stimulation-induced analgesia, spinal cord dorsal horn neuronal responses to graded mechanical stimuli were recorded. VTA stimulation significantly inhibited dorsal horn neuronal activity in response to pressure and pinch from the paw, but not brush. This indicated that VTA stimulation may have exerted its analgesic effect via descending modulatory pain pathways, possibly through its connections with brain stem structures and cerebral cortex areas.

Stimulation of the ventral tegmental area increased nociceptive thresholds and decreased spinal dorsal horn neuronal activity in rat

Local field potentials in the ventral tegmental area during cocaine-induced locomotor activation: Measurements in freely moving rats

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Stimulation of the ventral tegmental area increased nociceptive thresholds and decreased spinal dorsal horn neuronal activity in rat

Local field potentials in the ventral tegmental area during cocaine-induced locomotor activation: Measurements in freely moving rats