Arnold Kriegstein, MD, PhD, on HPPD

Dr. Kriegstein received BA from Yale University and his MD and PhD degrees from New York University in 1977 where his thesis advisor was Dr. Eric Kandel. He subsequently completed Residency training in Neurology at the Brigham and Women’s Hospital, Children’s Hospital, and Beth Israel Hospital in Boston. He has held academic appointments at Stanford University, Yale University, and Columbia University. In 2004 he joined the Neurology Department at the University of California, San Francisco. He is currently the John Bowes Distinguished Professor in Stem Cell and Tissue Biology and Founding Director of the Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research at UCSF. Dr. Kriegstein’s own research focuses on the way in which neural stem and progenitor cells in the embryonic brain produce neurons, and ways in which this information can be used for cell based therapies to treat diseases of the nervous system. His lab found that radial glial cells are neuronal stem cells in the developing brain, and also identified a second type of precursor cell produced by radial glial cells that is responsible for generating specific neuronal subtypes. He has recently begun to characterize the progenitor cells within the developing human brain, to determine the genetic profiles of specific progenitor populations, and to explore how these cells contribute to the huge expansion of neuron number that characterizes human cerebral cortex.

His theory on HPPD is as follows:

The thalamic filter and integrator model. The thalamus, within limbic cortico–striato–(pallido)–thalamo–cortical (CSTC) feedback loops, is proposed to function as a filter in the gating of extero- and interoceptive sensory and cognitive information to the cortex and, within cortico–thalamo–cortical (CTC) re-entrant pathways, it is proposed to be crucial in integrating cortically categorized exteroceptive perception with internal stimuli of the memory and value system.

Thalamic gating is under the control of glutamatergic cortico–striatal pathways projecting to the dorsomedial (MD) and reticular nuclei of the thalamus and under the modulatory influence of serotonergic and dopaminergic projections arising from the raphe and ventral tegmentum (VTA) to several components of the CSTC loops. The model predicts that serotonergic hallucinogens disrupt thalamic gating and produce sensory overload of the prefrontal cortex by excessive stimulation of 5-HT2A receptors located in several components of the CSTC loop, including the prefrontal cortex , limbic striatum and thalamus. The blockade of NMDA-mediated glutamatergic (Glu) cortico–striatal neurotransmission (e.g. by ketamine) or the increase of mesolimbic dopaminergic (DA) neurotransmission (e.g. by D-amphetamine) could lead to a similar neurotransmitter imbalance in CSTC loops, which again results in an opening of the thalamic filter, sensory overload of the cortex and psychosis.

In addition, the excessive stimulation of thalamic and/or cortical 5-HT2A receptors located on GABAergic interneurons by hallucinogens could lead to a disruption of CTC or cortico–cortical integration of distributed neuronal activity (‘binding’), which, in turn, might underlie the more anxious and fragmented experience of egodissolution that is often reported after high doses of hallucinogens. Although application of serotonergic hallucinogens into the frontal cortex in rodents has been demonstrated to increase pyramidal-cell activity via stimulation of 5-HT2A receptors located on apical dendrites of pyramidal cells and/or GABAergic neurons, it remains unclear whether such a local activation without a subsequent disruption of thalamic gating or integration of information processing leads to psychosis in humans or simply to excitation and/or increased sensory awareness.

Abbreviations: VTA, ventral tegmental area; AMY, amygdala; HPC, hippocampus; 5-HT, serotonin, DA,dopamine, Glu, glutamate; receptors: 2A, 5-HT2A; 1A, 5-HT1A; mGlu2/3, metabotropic glutamate receptor subtypes 2 and 3; NMDA, N-methyl-D-aspartate; D2, dopamine D2.


Arnold Kriegstein Profile