The Cerebral Localization of Pain: Anatomical and Functional Considerations for Targeted Electrical Therapies

Abstract

Millions of people in the United States are affected by chronic pain, and the financial cost of pain treatment is weighing on the healthcare system. In some cases, current pharmacological treatments may do more harm than good, as with the United States opioid crisis. Direct electrical stimulation of the brain is one potential non-pharmacological treatment with a long history of investigation. Yet brain stimulation has been far less successful than peripheral or spinal cord stimulation, perhaps because of our limited understanding of the neural circuits involved in pain perception. In this paper, we review the history of using electrical stimulation of the brain to treat pain, as well as contemporary studies identifying the structures involved in pain networks, such as the thalamus, insula, and anterior cingulate. We propose that the thermal grill illusion, an experimental pain model, can facilitate further investigation of these structures. Pairing this model with intracranial recording will provide insight toward disentangling the neural correlates from the described anatomic areas. Finally, the possibility of altering pain perception with brain stimulation in these regions could be highly informative for the development of novel brain stimulation therapies for chronic pain.

Keywords: closed loop; deep brain stimulation; electrophysiology; imaging; neurophysiology; pain; sensing; thermal grill.

Figure 1

Overlay of three color-coded pain-related terms. “Chronic pain” is blue, “painful” is yellow, and “pain” is red. Functional magnetic resonance imaging (fMRI) studies of these terms are visualized in coronal (a), axial (b), and sagittal (c) axes from the Neurosynth database (neurosynth.org), showing consistent activation of the anterior cingulate cortex (ACC), thalamus, insula, and brainstem.

Figure 2

Descending pain modulatory pathway. The pathway originates in the cerebrum and descends to the periaqueductal gray (PAG) matter, rostral ventromedial medulla, and projects to the dorsal horn of the spinal cord. Bidirectional nociceptive pathways through the medullary nuclei are shown. The efferent pathway from the dorsal horn goes through the parabrachial nucleus, amygdala, and thalamic nuclei.

Figure 3

Rendering of a thermal grill interface and infrared images demonstrating patterns of warm and cool temperatures. Drawing (a) is representative of the interface that our group constructed. The top of the interface consists of six copper bars. Each bar is 1.0 cm in length and the bars are spaced 0.15 cm apart. The width of the six-bar interface is 9.8 cm. The electronic components fit inside the labeled compartment next to the fans, which allow for necessary air flow. Each bar is connected to a Peltier device, allowing for programmable temperature control (pink and blue coloring represents bars programmed to warm and cool temperatures, respectively). Infrared images acquired using the device are shown in (b). Left (b) shows all bars set to a cool temperature close to 20.0 °C. Middle (b) shows all bars set to a warm temperature close 40.0 °C. Right (b) shows one bar set at 20.0 °C and another bar near 40.0 °C. The alternating temperature setting is used to produce the pain illusion.