Features and timing of the response of single neurons to novelty in the substantia nigra

Mikell, Charles B.; Sheehy, John P.; Youngerman, Brett E.; McGovern, Robert A.; Wojtasiewicz, Teresa; Chan, Andrew K.; Pullman, Seth L.; Yu, Qiping; Goodman, Robert; Schevon, Catherine A.; McKhann, Guy M.

doi:10.1016/j.brainres.2013.10.033

Cited by 22 publications

(20 citation statements)

References 27 publications

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“…Additionally, we found that the degree of coordination of the activity of SN neurons with frontal theta frequency oscillations was predictive of successful memory formation. Although previous work shows that human SN neurons respond to reward prediction errors [ 14 ] and infrequent sounds in an odd-ball paradigm [ 16 ], our data are, to our knowledge, the first study describing SN neuronal activity during declarative memory formation in humans.…”

Section: Discussionmentioning

confidence: 65%

“…Studying how SN/VTA dopaminergic neurons signal reward and reward expectation errors [ 12 – 14 ] has revealed a mechanistic understanding of the role of the SN/VTA in classical conditioning and reinforcement learning [ 15 ]. In addition, in humans, SN neurons also respond to infrequent sounds in an odd-ball paradigm [ 16 ] and encode decision outcomes [ 17 ]. In contrast, little is known about the role of SN/VTA in the acquisition of declarative memories.…”

Section: Introductionmentioning

confidence: 99%

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Novelty-Sensitive Dopaminergic Neurons in the Human Substantia Nigra Predict Success of Declarative Memory Formation

et al. 2018

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Summary The encoding of information into long-term declarative memory is facilitated by dopamine. This process depends on hippocampal novelty signals, but it remains unknown how midbrain dopaminergic neurons are modulated by declarative-memory-based information. We recorded individual substantia nigra (SN) neurons and cortical field potentials in human patients performing a recognition memory task. We found that 25% of SN neurons were modulated by stimulus novelty. Extracellular waveform shape and anatomical location indicated that these memory-selective neurons were putatively dopaminergic. The responses of memory-selective neurons appeared 527 ms after stimulus onset, changed after a single trial, and were indicative of recognition accuracy. SN neurons phase locked to frontal cortical theta-frequency oscillations, and the extent of this coordination predicted successful memory formation. These data reveal that dopaminergic neurons in the human SN are modulated by memory signals and demonstrate a progression of information flow in the hippocampal-basal ganglia-frontal cortex loop for memory encoding.

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Section: Discussionmentioning

confidence: 65%

Section: Introductionmentioning

confidence: 99%

Novelty-Sensitive Dopaminergic Neurons in the Human Substantia Nigra Predict Success of Declarative Memory Formation

et al. 2018

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“…While the neural mechanisms underlying this phenomenon remain poorly understood, some studies have implicated the attentional M3 (or P3 in EEG studies) signal in association with the TOE (Shapiro et al 2006;Hairston and Nagarajan 2007). Indeed, recent findings by our group have implicated midbrain DA neurons underlying the M3/P3 signal in an auditory oddball task (Mikell et al 2014). The TOE may thus be a reflection of greater attentional resources being devoted to the more recent stimulus.…”

Section: Discussionmentioning

confidence: 88%

“…Indeed, recent findings by our group have implicated midbrain DA neurons underlying the M3/P3 signal in an auditory oddball task (Mikell et al. 2014). The TOE may thus be a reflection of greater attentional resources being devoted to the more recent stimulus.…”

Section: Discussionmentioning

confidence: 99%

Human substantia nigra neurons encode decision outcome and are modulated by categorization uncertainty in an auditory categorization task

et al. 2015

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The ability to categorize stimuli – predator or prey, friend or foe – is an essential feature of the decision-making process. Underlying that ability is the development of an internally generated category boundary to generate decision outcomes. While classic temporal difference reinforcement models assume midbrain dopaminergic neurons underlie the prediction error required to learn boundary location, these neurons also demonstrate a robust response to nonreward incentive stimuli. More recent models suggest that this may reflect a motivational aspect to performing a task which should be accounted for when modeling dopaminergic neuronal behavior. To clarify the role of substantia nigra dopamine neurons in uncertain perceptual decision making, we investigated their behavior using single neuron extracellular recordings in patients with Parkinson's disease undergoing deep brain stimulation. Subjects underwent a simple auditory categorical decision-making task in which they had to classify a tone as either low- or high-pitched relative to an explicit threshold tone and received feedback but no reward. We demonstrate that the activity of human SN dopaminergic neurons is predictive of perceptual categorical decision outcome and is modulated by uncertainty. Neuronal activity was highest during difficult (uncertain) decisions that resulted in correct responses and lowest during easy decisions that resulted in incorrect responses. This pattern of results is more consistent with a “motivational” role with regards to perceptual categorization and suggests that dopamine neurons are most active when critical information – as represented by uncertainty – is available for learning decision boundaries.

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“…102 This biphasic response was recently replicated in humans. 82 These phasic changes reverberate within the circuit, and, at higher cortical levels (or, as Kapur puts it, the "mind level"), the net result of all of this signal integration is an assignment of relative salience to a stimulus. 53 In psychosis, it is proposed that dysregulation of the tonic-phasic dopaminergic system results initially in misattributions of reward to stimuli that would otherwise be ignored, resulting in aberrant salience at those higher cortical levels, and finally manifesting clinically as the positive symptoms of schizophrenia, including delusions and hallucinations.…”

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confidence: 99%

Neurosurgery for schizophrenia: an update on pathophysiology and a novel therapeutic target

Mikell

Sinha

Sheth

2016

JNS

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Schizophrenia is a heterogeneous disorder characterized by varying degrees of positive psychotic symptoms, negative symptoms, and cognitive impairment. 48 With a prevalence of 1.1% in the US, 93 schizophrenia is a major health burden, increasing the risk for numerous adverse outcomes, including the inability to maintain a stable residence, maintain a job, or find a spouse. 39Moreover, 10%-30% of patients with schizophrenia have little or no response to antipsychotic treatment. 68 Limited treatment options are available after first-line therapies have failed. Potential therapies for refractory schizophrenia include clozapine, electroconvulsive therapy, and repetitive transcranial magnetic stimulation (rTMS), but many patients continue to have symptoms despite maximal medical management.57 New treatment strategies are therefore needed.Although deep brain stimulation (DBS) is chiefly used in the treatment of movement disorders, its use in behavioral disorders is expanding. In 2009, the FDA awarded DBS a humanitarian device exemption (HDE) for obsessive-compulsive disorder (OCD). Given preliminary evidence of efficacy in OCD, 29,33,69,91 the use of DBS to treat other psychiatric disorders, including depression, Tourette syndrome, and even autism, is expanding. 111 Currently, interest in treating schizophrenia using DBS is growing, and a clinical trial is now open in Canada for the treatment of refractory schizophrenia. 16 Moreover, the growing use of DBS for behavioral indications has been accompanied by an expansion in understanding of the underlying pathophysiology of psychiatric disease. In the case of schizophrenia, there is increasing acceptance that the disorder is characterized by dysfunction in the hippocampus and striatum, suggesting possible targets for intervention. 54Given our increasing understanding of the neuroanatomy of schizophrenia, the time is ripe for the development of novel circuit-based therapies, including DBS.abbreviatioNs AST = associative striatum; BOLD = blood oxygen level-dependent; cSP = cortical silent period; DBS = deep brain stimulation; DLPFC = dorsolateral prefrontal cortex; fMRI = functional MRI; GABA = gamma-aminobutyric acid; HDE = humanitarian device exemption; MDD = major depressive disorder; NMDA = N-methyl-daspartate; OCD = obsessive-compulsive disorder; rCBF = regional cerebral blood flow; rTMS = repetitive TMS; SICI = short-interval intracortical inhibition; TMS = transcranial magnetic stimulation; VBM = voxel-based morphometry; VS = ventral striatum; VTA = ventral tegmental area. The main objectives of this review were to provide an update on the progress made in understanding specific circuit abnormalities leading to psychotic symptoms in schizophrenia and to propose rational targets for therapeutic deep brain stimulation (DBS). Refractory schizophrenia remains a major unsolved clinical problem, with 10%-30% of patients not responding to standard treatment options. Progress made over the last decade was analyzed through reviewing structural and functional neuroimaging s...

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Features and timing of the response of single neurons to novelty in the substantia nigra

Cited by 22 publications

References 27 publications

Novelty-Sensitive Dopaminergic Neurons in the Human Substantia Nigra Predict Success of Declarative Memory Formation

Novelty-Sensitive Dopaminergic Neurons in the Human Substantia Nigra Predict Success of Declarative Memory Formation

Human substantia nigra neurons encode decision outcome and are modulated by categorization uncertainty in an auditory categorization task

Neurosurgery for schizophrenia: an update on pathophysiology and a novel therapeutic target

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