Despite adequate dietary management, patients with Classic Galactosemia continue to have increased risks of cognitive deficits, speech dyspraxia, primary ovarian insufficiency, and abnormal motor development. A recent evaluation of a new galactose-1 phosphate uridylyltransferase (GALT)-deficient mouse model revealed reduced fertility and growth restriction. These phenotypes resemble those seen in human patients. In this study, we further assess the fidelity of this new mouse model by examining the animals for the manifestation of a common neurological sequela in human patients: cerebellar ataxia. The balance, grip strength, and motor coordination of GALT-deficient and wild-type mice were tested using a modified rotarod. The results were compared to composite phenotype scoring tests, typically used to evaluate neurological and motor impairment. The data demonstrated abnormalities with varying severity in the GALT-deficient mice. Mice of different ages were used to reveal the progressive nature of motor impairment. The varying severity and age-dependent impairments seen in the animal model agree with reports on human patients. Finally, measurements of the cerebellar granular and molecular layers suggested that mutant mice experience cerebellar hypoplasia, which could have resulted from the down-regulation of the PI3K/Akt signaling pathway.

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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.

Pain is a complex experience involving sensory, emotional, and cognitive aspects, and multiple networks manage its processing in the brain. Examining how pain transforms into a behavioral response can shed light on the networks' relationships and facilitate interventions to treat chronic pain. However, studies using high spatial and temporal resolution methods to investigate the neural encoding of pain and its psychophysical correlates have been limited. We recorded from intracranial stereo-EEG (sEEG) electrodes implanted in sixteen different brain regions of twenty patients who underwent psychophysical pain testing consisting of a tonic thermal stimulus to the hand. Broadband high-frequency local field potential amplitude (HFA; 70-150 Hz) was isolated to investigate the relationship between the ongoing neural activity and the resulting psychophysical pain evaluations. Two different generalized linear mixed-effects models (GLME) were employed to assess the neural representations underlying binary and graded pain psychophysics. The first model examined the relationship between HFA and whether the patient responded "yes" or "no" to whether the trial was painful. The second model investigated the relationship between HFA and how painful the stimulus was rated on a visual analog scale. GLMEs revealed that HFA in the inferior temporal gyrus (ITG), superior frontal gyrus (SFG), and superior temporal gyrus (STG) predicted painful responses at stimulus onset. An increase in HFA in the orbitofrontal cortex (OFC), SFG, and striatum predicted pain responses at stimulus offset. Numerous regions including the anterior cingulate cortex, hippocampus, IFG, MTG, OFC, and striatum, predicted the pain rating at stimulus onset. However, only the amygdala and fusiform gyrus predicted increased pain ratings at stimulus offset. We characterized the spatiotemporal representations of binary and graded painful responses during tonic pain stimuli. Our study provides evidence from intracranial recordings that the neural encoding of psychophysical pain changes over time during a tonic thermal stimulus, with different brain regions being predictive of pain at the beginning and end of the stimulus.