Jong H. Yoon, MD, is a clinician-scientist who is focused on applying novel neuroimaging methods to discover the brain mechanisms of schizophrenia and stimulant abuse disorder, as well as developing mechanism based treatments for these conditions. He is dually appointed at the Palo Alto VA, where he serves as the Director of the Repetitive Transcranial Magnetic Stimulation (rTMS) Neuromodulation Clinic. As a cognitive neuroscientist, he has led a number of federally funded projects developing and utilizing advanced in vivo neuroimaging methods. HIs work is particularly interested in investigating impairments in the function of the basal ganglia, which gives rise to cognitive and information processing deficits and psychosis in schizophrenia and other psychiatric conditions. Towards these ends, he has been developing novel fMRI methods to accurately measure the functional properties of basal ganglia nuclei. Dr. Yoon is also developing new neuroimaging approaches for indexing brain function and dysfunction, including methods for measuring task-evoked GABA levels in the brain and applying a newly developed PET tracer for determining synaptic health in humans and in disease. He received his medical degree from the New York University School of Medicine and residency training in adult psychiatry at the Langley Porter Psychiatric Institute at University of California San Francisco. He completed a post-doctoral fellowship in cognitive neuroscience and functional neuroimaging at University of California Berkeley.
Director, Repetitive Transcranial Magnetiic Stimulation (rTMS) Neuromodulation Clinic, VA Palo Alto Health Care System, Palo Alto Division (2018 - Present)
Honors & Awards
NARSAD Young Investigator Award, Brain & Behavioral Research Foundation (7/1/11-6/30/13)
David Mahoney Neuroimaging Award, The Dana Foundation (5/1/14-4/30/17)
Boards, Advisory Committees, Professional Organizations
Editorial Board Member, Biological Psychiatry: Cognitive Neuroscience Neuroimaging (2018 - Present)
BA, Swarthmore College, Sociology/Anthropology (1990)
MD, New York University School of Medicine, Medicine with Honors (1995)
Medical Student Fellow, Howard Hughes Medical Institute - National Institutes of Health (HHMI-NIH), Research Scholars Program (1994)
Internship, University of California San Francisco (1996)
Residency, Langley Porter Psychiatric Institute - University of California San Francisco, Psychiatry (1999)
Board Certification, American Board of Psychiatry and Neurology, Psychiatry (1999)
Post-Doctoral Fellowship, University of California Berkeley, Cognitive Neuroscience/Functional Neuroimaging (2005)
Current Research and Scholarly Interests
My research seeks to discover the brain mechanisms responsible for schizophrenia and to translate this knowledge into the clinic to improve how we diagnose and treat this condition. Towards these ends, our group has been developing cutting-edge neuroimaging tools to identify neurobiological abnormalities and test novel systems-level disease models of psychosis and schizophrenia directly in individuals with these conditions.
We have been particularly interested in the role of neocortical-basal ganglia circuit dysfunction. A working hypothesis is that some of the core symptoms of schizophrenia are attributable to impairments in neocortical function that results in disconnectivity with components of the basal ganglia and dysregulation of their activity. The Yoon Lab has developed new high-resolution functional magnetic resonance imaging methods to more precisely measure the function of basal ganglia components, which given their small size and location deep within the brain has been challenging. This includes ways to measure the activity of nuclei that store and control the release of dopamine throughout the brain, a neurochemical that is one of the most important factors in the production of psychosis in schizophrenia and other neuropsychiatric conditions.
Does rTMS Induce Synaptic Plasticity?
The purpose of this study is to utilize the radioactive positron emission tomography (PET) tracer [11C]UCB-J to investigate the effect of repetitive transcranial magnetic stimulation (rTMS) on synaptic plasticity. UCB-J has been validated as a marker for synaptic density. We will use this tracer to examine if rTMS leads to changes in synaptic plasticity, specifically changes in synaptic density, in individuals receiving rTMS for MDD. If rTMS is proven effective for increasing synaptic plasticity, there is a significant potential of a new applicable treatment for a variety of diseases that affect brain physiology.
Stanford is currently not accepting patients for this trial.
Imaging Synapses With [11C] UCB-J in the Human Brain
The purpose of this study is to utilize the radioactive positron emission tomography (PET) tracer [11C]UCB-J to test the neural synaptic pruning hypothesis of schizophrenia. This imaging method allows for the quantification of synaptic density in the living human brain and has the unprecedented ability to directly examine the synaptic pathology underlying neuropsychiatric disease. The neural synaptic pruning hypothesis posits that a key pathogenic process of schizophrenia is the over-exuberant elimination of neural synapses during development. The confirmation of reduced synaptic density in schizophrenia as evidenced by [11C]UCB-J has the potential to lead to a number of ground-breaking clinical innovations, such as laboratory-based diagnostics and prognostics, and novel, disease-modifying treatments.
Stanford is currently not accepting patients for this trial.
Treating Stimulant Addiction With Repetitive Transcranial Magnetic Stimulation
The purpose of this study is to establish a new treatment (repetitive transcranial stimulation (rTMS)) for Veterans with stimulant use disorder (SUD). Despite the large public health burden imposed by SUD, there is currently no FDA-approved or widely recognized effective somatic treatment. rTMS may be a promising treatment option for SUD. In this study, we will demonstrate the feasibility of applying rTMS to Veterans with SUD, examine the efficacy of rTMS in the treatment of SUD, and explore biomarkers that may guide patient selection for rTMS treatment and predict treatment response.
Stanford is currently not accepting patients for this trial. For more information, please contact Jong H Yoon, MD, 650-493-5000.
A Clinical Program to Implement Repetitive Transcranial Magnetic Stimulation for Depression in the Department of Veterans Affairs.
Federal practitioner : for the health care professionals of the VA, DoD, and PHS
2020; 37 (6): 276–81
Repetitive transcranial magnetic stimulation (rTMS) uses a device to create magnetic fields that cause electrical current to flow into targeted neurons in the brain. The most common clinical use of rTMS is for the treatment of major depressive disorder (MDD). The annual suicide rate of veterans has been higher than the national average; treating depression with rTMS would likely decrease suicide risk. MDD in many patients can be chronic and reoccurring with medication and psychotherapy providing inadequate relief.A pilot program was created to supply rTMS devices to 35 different sites in the VA nationwide in order to treat treatment-resistant depression.At time of analysis more than 950 veterans have started the program and 412 have finished. Nationwide, we have seen the depression scores decline, indicating an improvement in well-being. In addition, there is high patient satisfaction. Collecting data on a national level is a powerful way to examine rTMS efficacy and predictors of response which might be lost on a smaller subset of cases.
View details for PubMedID 32669780
View details for PubMedCentralID PMC7357884
Transcranial Magnetic Stimulation: A Clinical Primer for Nonexperts.
Journal of psychiatric practice
2020; 26 (5): 423–28
Transcranial magnetic stimulation (TMS) is a safe and effective therapeutic modality for a rapidly expanding range of neuropsychiatric indications. Among psychiatric conditions, it is presently approved by the US Food and Drug Administration for treatment-resistant unipolar major depressive disorder and obsessive-compulsive disorder, 2 highly prevalent conditions with a considerable public health impact. There is also mounting evidence for its clinical utility in numerous other neuropsychiatric conditions. Nonetheless, many mental health providers, as well as primary care and other providers, remain unfamiliar with its clinical use. In this primer, we seek to describe in nontechnical terms how the magnetic field is applied to the brain, the unmet needs that may be remediated with TMS, the present state of evidence for clinical effectiveness, particularly in major depressive disorder, the safety profile of TMS, what patients experience during TMS, and some recent developments that serve to advance the use of this still novel intervention. TMS is poised to assume an important place in the armamentarium of interventions to better serve our patients, especially those with serious, chronic conditions with high rates of resistance to more conventional treatments. Consequently, it is essential that mental health providers gain as adequate a working knowledge of device-based interventions such as TMS as they currently have of psychopharmacological and psychosocial interventions. Among other potential benefits, this information should aid the process of obtaining informed consent from patients who are candidates for these treatments.
View details for DOI 10.1097/PRA.0000000000000490
View details for PubMedID 32936590
- Transcranial Magnetic Stimulation: A Clinical Primer for Non-Experts Journal of Psychiatric Practice 2020
Reduced invivo visual cortex GABA in schizophrenia, a replication in a recent onset sample.
The GABA deficit hypothesis remains one of the most compelling explanations for the information processing impairments in schizophrenia. However, much of the supportive evidence has been derived from post-mortem studies, whereas invivo studies have largely yielded inconsistent results. We undertook this single voxel proton magnetic resonance (MRS) GABA study to test in a sample of recent onset patients the replicability of our prior finding of reduced early visual cortex GABA in schizophrenia. We also examined the possibility that antipsychotics could represent a significant confound by studying a small subsample of antipsychotic naive subjects. 23 adults with recent onset schizophrenia and a demographically matched sample of 31 healthy control subjects underwent MRS using a MEGA PRESS sequence on a 3T MR scanner to measure GABA concentration in early visual cortex. To control for in-scanner head movement confounding the results, we quantified the amount of head movement during GABA scans to identify and exclude from analysis scans with excessive movement. Patients demonstrated significantly reduced GABA levels compared to control subjects, p = 0.029. GABA levels did not differ significantly between patients who were antipsychotic naive (n=7) and patients treated with antipsychotics. This replication in a recent onset sample suggest that diminished GABA in the visual cortex is a reliable finding, present in early phase of illness and not confounded by illness chronicity.
View details for DOI 10.1016/j.schres.2019.10.025
View details for PubMedID 31704157
- Psychotic symptoms in youth with Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) may reflect syndrome severity and heterogeneity (vol 110, pg 93, 2019) JOURNAL OF PSYCHIATRIC RESEARCH 2019; 113: 45
- Impaired prefrontal functional connectivity associated with working memory task performance and disorganization despite intact activations in schizophrenia PSYCHIATRY RESEARCH-NEUROIMAGING 2019; 287: 10–18
Subthalamic Nucleus Activation Occurs Early during Stopping and Is Associated with Trait Impulsivity.
Journal of cognitive neuroscience
The subthalamic nucleus (STN) is thought to be a central regulator of behavioral inhibition, and behavioral inhibition is thought to be a major determinant of impulsivity. Thus, it would be reasonable to hypothesize that STN function is related to impulsivity. However, it has been difficult to test this hypothesis due to the challenges in noninvasively and accurately measuring this structure's signal in humans. We utilized a novel approach for STN signal localization that entails identifying this structure directly on fMRI images for each individual participant in native space. Using this approach, we measured STN responses during the stop signal task in a sample of healthy adult participants. We confirmed that the STN exhibited selective activation during "Stop" trials. Furthermore, the magnitude of STN activation during successful Stop trials inversely correlated with individual differences in trait impulsivity as measured by a personality inventory. Time course analysis revealed that early STN activation differentiated successful from unsuccessful Stop trials, and individual differences in the magnitude of STN activation inversely correlated with stop signal RT, an estimate of time required to stop. These results are consistent with the STN playing a central role in inhibition and related behavioral proclivities, with implications for both normal range function and clinical syndromes of inhibitory dyscontrol. Moreover, the methods utilized in this study for measuring STN fMRI signal in humans may be gainfully applied in future studies to further our understanding of the role of the STN in regulating behavior and neuropsychiatric conditions.
View details for PubMedID 30605003
Psychotic symptoms in youth with Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) may reflect syndrome severity and heterogeneity.
Journal of psychiatric research
2018; 110: 93–102
OBJECTIVE: In the clinical syndrome Pediatric Acute-onset Neuropsychiatric Syndrome (PANS), obsessive compulsive disorder (OCD) and/or food refusal symptoms have an abrupt-onset (over 48 h) coupled with at least two other specified neuropsychiatric symptoms. We aimed to characterize in detail for the first time, psychotic symptoms experienced by children with PANS as well as the impact of psychotic symptoms on disease severity and course of illness. We inform about the diagnosis of the clinical description: PANS and hope to improve evaluation, treatment, diagnostic validity and future investigation.METHODS: Retrospective review of 143 consecutive PANS clinic patient charts meeting inclusion criteria. The Caregiver Burden Inventory, Global Impairment Score, and Children's Global Assessment Scale were used to assess impairment.RESULTS: Visual and auditory hallucinations were each experienced by 36%, of which most (83%) were transient and complex (non-threatening voices or figures). 6.3% and 5.5% of patients experienced delusions and thought disorganization respectively. Those with psychotic symptoms showed statistically significant differences in disease impairment and caregiver burden. There were no differences in time to treatment access or length of illness.CONCLUSIONS: Over 1/3 of children with PANS experienced transient hallucinations. They were more impaired than those without psychotic symptoms, but showed no differences in disease progression. This difference may point toward heterogeneity in PANS. When evaluating children with acute psychotic symptoms, clinicians should screen for abrupt-onset of a symptom cluster including OCD and/or food refusal, with neuropsychiatric symptoms (enuresis, handwriting changes, tics, hyperactivity, sleep disorder) before initiating treatment.
View details for PubMedID 30605785
Altered brainstem responses to modafinil in schizophrenia: implications for adjunctive treatment of cognition
2018; 8: 58
Candidate pro-cognitive drugs for schizophrenia targeting several neurochemical systems have consistently failed to demonstrate robust efficacy. It remains untested whether concurrent antipsychotic medications exert pharmacodynamic interactions that mitigate pro-cognitive action in patients. We used functional MRI (fMRI) in a randomized, double-blind, placebo-controlled within-subject crossover test of single-dose modafinil effects in 27 medicated schizophrenia patients, interrogating brainstem regions where catecholamine systems arise to innervate the cortex, to link cellular and systems-level models of cognitive control. Modafinil effects were evaluated both within this patient group and compared to a healthy subject group. Modafinil modulated activity in the locus coeruleus (LC) and ventral tegmental area (VTA) in the patient group. However, compared to the healthy comparison group, these effects were altered as a function of task demands: the control-independent drug effect on deactivation was relatively attenuated (shallower) in the LC and exaggerated (deeper) in the VTA; in contrast, again compared to the comparison group, the control-related drug effects on positive activation were attenuated in LC, VTA and the cortical cognitive control network. These altered effects in the LC and VTA were significantly and specifically associated with the degree of antagonism of alpha-2 adrenergic and dopamine-2 receptors, respectively, by concurrently prescribed antipsychotics. These sources of evidence suggest interacting effects on catecholamine neurons of chronic antipsychotic treatment, which respectively increase and decrease sustained neuronal activity in LC and VTA. This is the first direct evidence in a clinical population to suggest that antipsychotic medications alter catecholamine neuronal activity to mitigate pro-cognitive drug action on cortical circuits.
View details for DOI 10.1038/s41398-018-0104-z
View details for Web of Science ID 000428350300004
View details for PubMedID 29507283
View details for PubMedCentralID PMC5838154
Early interventions in a US military FIRST episode psychosis program.
Early intervention in psychiatry
Naval Medical Center San Diego's Psychiatric Transition Program is a specialized first episode psychosis treatment program that delivers coordinated specialty care to military service members with psychotic disorders. Due to the unique military environment, military service members with first episode psychosis are hypothesized to receive care very early after the emergence of first psychotic symptoms, resulting in significantly reduced duration of untreated psychosis. This study's aim is to calculate the duration of untreated psychosis for patients enrolled in Naval Medical Center San Diego's Psychiatric Transition Program (NMCSD PTP) from 01JUL2014-31DEC2016.Patients included in this study had a diagnosis of schizophreniform disorder (13.04%), schizophrenia (43.48%), schizoaffective disorder (8.70%), other specified schizophreniform disorder (30.43%), or brief psychotic disorder (4.35%) upon discharge from military service and NMCSD PTP. Duration of untreated psychosis was defined as the interval from emergence of positive psychotic symptoms to antipsychotic medication initiation. Duration of untreated psychosis was measured through retrospective review of the electronic medical record. A total of 69 subjects in the Naval Medical Center San Diego's Psychiatric Transition Program met inclusion criteria. Mean and median values as well as standard deviations were calculated for all included subjects.The mean duration to scheduled (non-PRN) neuroleptic medication was 37 days (median: 4 days). The mean duration to PRN neuroleptic medication was 21 days (median: 2 days).These data support our view that the structure of the military and military healthcare system markedly shortens the DUP for military service members who experience first episode psychosis.
View details for PubMedID 29971958
- Automatic Detection of Incoherent Speech for Diagnosing Schizophrenia Computational Linguistics and Clinical Psychology Workshop 2018
Dorsolateral Prefrontal Cortex GABA Concentration in Humans Predicts Working Memory Load Processing Capacity
JOURNAL OF NEUROSCIENCE
2016; 36 (46): 11788-11794
The discovery of neural mechanisms of working memory (WM) would significantly enhance our understanding of complex human behaviors and guide treatment development for WM-related impairments found in neuropsychiatric conditions and aging. Although the dorsolateral prefrontal cortex (DLPFC) has long been considered critical for WM, we still know little about the neural elements and pathways within the DLPFC that support WM in humans. In this study, we tested whether an individual's DLPFC gamma-aminobutryic acid (GABA) content predicts individual differences in WM task performance using a novel behavioral approach. Twenty-three healthy adults completed a task that measured the unique contribution of major WM components (memory load, maintenance, and distraction resistance) to performance. This was done to address the possibility that components have differing GABA dependencies and the failure to parse WM into components would lead to missing true associations with GABA. The subjects then had their DLPFC GABA content measured by single-voxel proton magnetic spectroscopy. We found that individuals with lower DLPFC GABA showed greater performance degradation with higher load, accounting for 31% of variance, p(corrected) = 0.015. This relationship was component, neurochemical, and brain region specific. DLPFC GABA content did not predict performance sensitivity to other components tested; DLPFC glutamate + glutamine and visual cortical GABA content did not predict load sensitivity. These results confirm the involvement of DLPFC GABA in WM load processing in humans and implicate factors controlling DLPFC GABA content in the neural mechanisms of WM and its impairments.This study demonstrated for the first time that the amount of gamma-aminobutryic acid (GABA), the major inhibitory neurotransmitter of the brain, in an individual's prefrontal cortex predicts working memory (WM) task performance. Given that WM is required for many of the most characteristic cognitive and behavioral capabilities in humans, this finding could have a significant impact on our understanding of the neural basis of complex human behavior. Furthermore, this finding suggests that efforts to preserve or increase brain GABA levels could be fruitful in remediating WM-related deficits associated with neuropsychiatric conditions.
View details for DOI 10.1523/JNEUROSCI.1970-16.2016
View details for Web of Science ID 000391056600020
View details for PubMedID 27852785
View details for PubMedCentralID PMC5125231
Sustained Modafinil Treatment Effects on Control-Related Gamma Oscillatory Power in Schizophrenia
2016; 41 (5): 1231-1240
Control-related cognitive processes such as rule selection and maintenance are associated with cortical oscillations in the gamma range, and modulated by catecholamine neurotransmission. Control-related gamma power is impaired in schizophrenia, and an understudied treatment target. It remains unknown whether pro-catecholamine pharmacological agents augment control-related gamma oscillations in schizophrenia. We tested the effects of 4-week fixed-dose daily adjunctive modafinil (MOD) 200 mg, in a randomized double-blind, placebo-controlled, parallel-groups design. Twenty-seven stable schizophrenia patients performed a cognitive control task during EEG, at baseline and after 4 weeks of treatment. EEG data underwent time-frequency decomposition with Morlet wavelets to determine power of 4-80 Hz oscillations. The modafinil group (n=14), relative to placebo group (n=13), exhibited enhanced oscillatory power associated with high-control rule selection in the gamma range after treatment, with additional effects during rule maintenance in gamma and sub-gamma ranges. MOD-treated patients who exhibited improved task performance with treatment also showed greater treatment-related delay period gamma compared with MOD-treated patients without improved performance. This is the first evidence in schizophrenia of augmentation of cognition-related gamma oscillations by an FDA-approved agent with therapeutic potential. Gamma oscillations represent a novel treatment target in this disorder, and modulation of catecholamine signaling may represent a viable strategy at this target.
View details for DOI 10.1038/npp.2015.271
View details for Web of Science ID 000371801200006
View details for PubMedID 26329382
View details for PubMedCentralID PMC4793107
A case of butane hash oil (marijuana wax)-induced psychosis
2016; 37 (3): 384-386
Marijuana is one of the most widely used controlled substances in the United States. Despite extensive research on smoked marijuana, little is known regarding the potential psychotropic effects of marijuana "wax," a high-potency form of marijuana that is gaining in popularity.The authors present a case of "Mr. B," a 34-year-old veteran who presented with profound psychosis in the setting of recent initiation of heavy, daily marijuana wax use. He exhibited incoherent speech and odd behaviors and appeared to be in a dream-like state with perseverating thoughts about his combat experience. His condition persisted despite treatment with risperidone 4 mg twice a day (BID), but improved dramatically on day 8 of hospitalization with the return of baseline mental function. Following discharge, Mr. B discontinued all marijuana use and did not exhibit the return of any psychotic symptoms.This study highlights the need for future research regarding the potential medical and psychiatric effects of new, high-potency forms of marijuana. Could cannabis have a dose-dependent impact on psychosis? What other potential psychiatric effects could emerge heretofore unseen in lower potency formulations? Given the recent legalization of marijuana, these questions merit timely exploration.
View details for DOI 10.1080/08897077.2016.1141153
View details for Web of Science ID 000382769800003
View details for PubMedID 26820171
- Control-related frontal-striatal function is associated with past suicidal ideation and behaviior in patients with recent-onset psychotic major mood disorders JOURNAL OF AFFECTIVE DISORDERS 2015; 188: 202-209
Delay Period Activity of the Substantia Nigra during Proactive Control of Response Selection as Determined by a Novel fMRI Localization Method
JOURNAL OF COGNITIVE NEUROSCIENCE
2015; 27 (6): 1238-1248
The ability to proactively control motor responses, particularly to overcome overlearned or automatic actions, is an essential prerequisite for adaptive, goal-oriented behavior. The substantia nigra (SN), an element of the BG, has figured prominently in current models of response selection. However, because of its small size and proximity to functionally distinct subcortical structures, it has been challenging to test the SN's involvement in response selection using conventional in vivo functional neuroimaging approaches. We developed a new fMRI localization method for directly distinguishing, on echo-planar images, the SN BOLD signal from that of neighboring structures, including the subthalamic nucleus (STN). Using this method, we tested the hypothesis that the SN supports the proactive control of response selection. We acquired high-resolution EPI volumes at 3 T from 16 healthy participants while they completed the Preparing to Overcome Prepotency task of proactive control. There was significantly elevated delay period signal selectively during high- compared with low-control trials in the SN. The STN did not show delay period activity in either condition. SN delay period signal was significantly inversely associated with task performance RTs across participants. These results suggest that our method offers a novel means for measuring SN BOLD responses, provides unique evidence of SN involvement in cognitive control in humans, and suggests a novel mechanism for proactive response selection.
View details for DOI 10.1162/jocn_a_00775
View details for Web of Science ID 000354111600014
View details for PubMedID 25514657
Conflict-related anterior cingulate functional connectivity is associated with past suicidal ideation and behavior in recent-onset schizophrenia
JOURNAL OF PSYCHIATRIC RESEARCH
2015; 65: 95-101
Suicide is highly prevalent in schizophrenia (SZ), yet it remains unclear how suicide risk factors such as past suicidal ideation or behavior relate to brain function. Circuits modulated by the prefrontal cortex (PFC) are altered in SZ, including in dorsal anterior cingulate cortex (dACC) during conflict-monitoring (an important component of cognitive control), and dACC changes are observed in post-mortem studies of heterogeneous suicide victims. We tested whether conflict-related dACC functional connectivity is associated with past suicidal ideation and behavior in SZ. 32 patients with recent-onset of DSM-IV-TR-defined SZ were evaluated with the Columbia Suicide Severity Rating Scale and functional MRI during cognitive control (AX-CPT) task performance. Group-level regression models relating past history of suicidal ideation or behavior to dACC-seeded functional connectivity during conflict-monitoring controlled for severity of depression, psychosis and impulsivity. Past suicidal ideation was associated with relatively higher functional connectivity of the dACC with the precuneus during conflict-monitoring. Intensity of worst-point past suicidal ideation was associated with relatively higher dACC functional connectivity in medial parietal lobe and striato-thalamic nuclei. In contrast, among those with past suicidal ideation (n = 17), past suicidal behavior was associated with lower conflict-related dACC connectivity with multiple lateral and medial PFC regions, parietal and temporal cortical regions. This study provides unique evidence that recent-onset schizophrenia patients with past suicidal ideation or behavior show altered dACC-based circuit function during conflict-monitoring. Suicidal ideation and suicidal behavior have divergent patterns of associated dACC functional connectivity, suggesting a differing pattern of conflict-related brain dysfunction with these two distinct features of suicide phenomenology.
View details for DOI 10.1016/j.jpsychires.2015.04.002
View details for Web of Science ID 000356123300013
View details for PubMedID 25891474
- Frontal Motor Cortex Activity During Reactive Control Is Associated With Past Suicidal Behavior in Recent-Onset Schizophrenia CRISIS-THE JOURNAL OF CRISIS INTERVENTION AND SUICIDE PREVENTION 2015; 36 (5): 363-370
- Modafinil Effects on Middle-Frequency Oscillatory Power During Rule Selection in Schizophrenia NEUROPSYCHOPHARMACOLOGY 2014; 39 (13): 3018-3026
- Task-evoked substantia nigra hyperactivity associated with prefrontal hypofunction, prefrontonigral disconnectivity and nigrostriatal connectivity predicting psychosis severity in medication naive first episode schizophrenia SCHIZOPHRENIA RESEARCH 2014; 159 (2-3): 521-526
Frontal cortex control dysfunction related to long-term suicide risk in recent-onset schizophrenia
2014; 157 (1-3): 19-25
Suicide is highly-prevalent and the most serious outcome in schizophrenia, yet the disturbances in neural system functions that confer suicide risk remain obscure. Circuits operated by the prefrontal cortex (PFC) are altered in psychotic disorders, and various PFC changes are observed in post-mortem studies of completed suicide. We tested whether PFC activity during goal-representation (an important component of cognitive control) relates to long-term suicide risk in recent-onset schizophrenia.35 patients with recent-onset of DSM-IV-TR-defined schizophrenia (SZ) were evaluated for long-term suicide risk (using the Columbia Suicide Severity Rating Scale) and functional MRI during cognitive control task performance. Group-level regression models associating control-related brain activation with suicide risk controlled for depression, psychosis and impulsivity.Within this group, past suicidal ideation was associated with lower activation with goal-representation demands in multiple PFC sectors. Among those with past suicidal ideation (n=18), reported suicidal behavior was associated with lower control-related activation in premotor cortex ipsilateral to the active primary motor cortex.This study provides unique evidence that suicide risk directly relates to PFC-based circuit dysfunction during goal-representation, in a major mental illness with significant suicide rates. Among those with suicidal ideation, the overt expression in suicidal behavior may stem from impairments in premotor cortex support of action-planning as an expression of control. Further work should address how PFC-based control function changes with risk over time, whether this brain-behavior relationship is specific to schizophrenia, and address its potential utility as a biomarker for interventions to mitigate suicide risk.
View details for DOI 10.1016/j.schres.2014.05.039
View details for Web of Science ID 000341314100004
View details for PubMedID 24972755
Modafinil augments oscillatory power in middle frequencies during rule selection
2014; 51 (6): 510-519
Control-related cognitive processes are associated with cortical oscillations and modulated by catecholamine neurotransmitters. It remains unclear how catecholamine systems modulate control-related oscillations. We tested modafinil effects on rule-related 4-30 Hz oscillations, with double-blind, placebo-controlled (within-subjects) testing of 22 healthy adults, using EEG during cognitive control task performance. EEG data underwent time-frequency decomposition with Morlet wavelets to determine power of 4-30 Hz oscillations. Modafinil enhanced oscillatory power associated with high-control rule selection in theta, alpha, and beta ranges, with a frontotemporal topography and minimal effects during rule maintenance. Augmentation of catecholamine signaling enhances middle-frequency cortical oscillatory power associated with rule selection, which may subserve diverse subcomponent processes in proactive cognitive control.
View details for DOI 10.1111/psyp.12201
View details for Web of Science ID 000335196300002
View details for PubMedID 24611660
Disrupted action monitoring in recent-onset psychosis patients with schizophrenia and bipolar disorder
2014; 221 (1): 114-121
Schizophrenia patients experience cognitive control disturbances, manifest in altered neural signatures during action monitoring. It remains unclear whether error- and conflict-monitoring disturbances co-occur, and whether they are observed in recent-onset psychosis patients with schizophrenia or bipolar disorder. We tested electrophysiological measures of action monitoring in these patients. Seventy-three schizophrenia patients (SZ), 26 bipolar disorder type I patients (BP), each within one year of psychosis onset, and 54 healthy control subjects (HC) underwent EEG during Stroop task performance. In the trial-averaged EEG at three midline scalp electrodes, the error-related negativity (ERN), error positivity (Pe) and conflict-related N450 were measured. Compared to HC (1) SZ exhibited an attenuated ERN and N450, and Pe unchanged and (2) BP exhibited an attenuated ERN but normal Pe and N450. Between patient groups, SZ showed an attenuated N450; ERN and Pe were not significantly different. A small (n=10) SZ subgroup that was not receiving antipsychotic medication showed normal ERPs. Altered error- and conflict-monitoring occur together in the first-episode schizophrenia patients, and these measures are comparable in patients with the first-episode bipolar disorder. Antipsychotic medication may be associated with altered measures of error-monitoring in schizophrenia.
View details for DOI 10.1016/j.pscychresns.2013.11.003
View details for Web of Science ID 000329459300017
View details for PubMedID 24314907
- Impaired context processing as a potential marker of psychosis risk state PSYCHIATRY RESEARCH-NEUROIMAGING 2014; 221 (1): 13-20
Task-evoked substantia nigra hyperactivity associated with prefrontal hypofunction, prefrontonigral disconnectivity and nigrostriatal connectivity predicting psychosis severity in medication naïve first episode schizophrenia.
2014; 159 (2-3): 521–26
The widely cited prefrontal dysfunction - excess subcortical dopamine model of schizophrenia posits that prefrontal deficits give rise to cognitive impairments and the disinhibition of subcortical dopamine release underlying psychosis. While this has been one of the most influential schizophrenia models, only a handful of studies have provided evidence supporting it directly in patients with schizophrenia. We previously demonstrated task-evoked substantia nigra hyperactivity in the context of prefrontal hypofunction and prefrontonigral functional disconnectivity. In addition, nigrostriatal functional connectivity was identified as a potential marker of psychosis. Because patients in this prior study had chronic schizophrenia and were treated with antipsychotics, in the present study we tested whether these findings were confounded by illness chronicity and medication effects by seeking to reproduce these findings in an independent sample of antipsychotic naïve, first episode (FE) patients. We compared event-related fMRI activations from 12 FE patients with 15 demographically matched healthy control subjects during cognitive testing. We found substantia nigra hyperactivity associated with prefrontal hypofunction and prefrontonigral functional disconnectivity, as well as the magnitude of nigrostriatal functional connectivity positively correlating with severity of psychosis. This study adds to the body of evidence supporting the prefrontal-dopamine model of schizophrenia and further validates nigrostriatal functional connectivity as a marker of psychosis.
View details for PubMedID 25266549
Modafinil effects on middle-frequency oscillatory power during rule selection in schizophrenia.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
2014; 39 (13): 3018–26
Control-related cognitive processes such as rule selection are associated with cortical oscillations in the theta, alpha and, beta ranges, and modulated by catecholamine neurotransmission. Thus, a potential strategy for improving cognitive control deficits in schizophrenia would be to use pro-catecholamine pharmacological agents to augment these control-related oscillations. In a double-blind, placebo-controlled (within-subjects) study, we tested the effects of adjunctive single-dose modafinil 200 mg on rule-related 4-30 Hz oscillations in 23 stable schizophrenia patients, using EEG during cognitive control task performance. EEG data underwent time-frequency decomposition with Morlet wavelets to determine the power of 4-30 Hz oscillations. Modafinil (relative to placebo) enhanced oscillatory power associated with high-control rule selection in theta, alpha, and beta ranges, with modest effects during rule maintenance. Modafinil treatment in schizophrenia augments middle-frequency cortical oscillatory power associated with rule selection, and may subserve diverse subcomponent processes in proactive cognitive control.
View details for PubMedID 24964814
View details for PubMedCentralID PMC4229573
Impaired Prefrontal-Basal Ganglia Functional Connectivity and Substantia Nigra Hyperactivity in Schizophrenia
2013; 74 (2): 122-129
The theory that prefrontal cortex (PFC) dysfunction in schizophrenia leads to excess subcortical dopamine has generated widespread interest because it provides a parsimonious account for two core features of schizophrenia, cognitive deficits and psychosis, respectively. However, there has been limited empirical validation of this model. Moreover, the identity of the specific subcortical brain regions and circuits that may be impaired as a result of PFC dysfunction and mediate its link to psychosis in schizophrenia remains unclear. We undertook this event-related functional magnetic resonance imaging study to test the hypothesis that PFC dysfunction is associated with altered function of and connectivity with dopamine regulating regions of the basal ganglia.Eighteen individuals with schizophrenia or schizoaffective disorder and 19 healthy control participants completed event-related functional magnetic resonance imaging during working memory. We conducted between-group contrasts of task-evoked, univariate activation maps to identify regions of altered function in schizophrenia. We also compared the groups on the level of functional connectivity between a priori identified PFC and basal ganglia regions to determine if prefrontal disconnectivity in patients was present.We observed task-evoked hyperactivity of the substantia nigra that occurred in association with prefrontal and striatal hypoactivity in the schizophrenia group. The magnitude of prefrontal functional connectivity with these dysfunctional basal ganglia regions was decreased in the schizophrenia group. Additionally, the level of nigrostriatal functional connectivity predicted the level of psychosis.These results suggest that functional impairments of the prefrontal striatonigral circuit may be a common pathway linking the pathogenesis of cognitive deficits and psychosis in schizophrenia.
View details for DOI 10.1016/j.biopsych.2012.11.018
View details for Web of Science ID 000321108800009
View details for PubMedID 23290498
Semantic processes leading to true and false memory formation in schizophrenia
2013; 147 (2-3): 320-325
Encoding semantic relationships between items on word lists (semantic processing) enhances true memories, but also increases memory distortions. Episodic memory impairments in schizophrenia (SZ) are strongly driven by failures to process semantic relations, but the exact nature of these relational semantic processing deficits is not well understood. Here, we used a false memory paradigm to investigate the impact of implicit and explicit semantic processing manipulations on episodic memory in SZ. Thirty SZ and 30 demographically matched healthy controls (HC) studied Deese/Roediger-McDermott (DRM) lists of semantically associated words. Half of the lists had strong implicit semantic associations and the remainder had low strength associations. Similarly, half of the lists were presented under "standard" instructions and the other half under explicit "relational processing" instructions. After study, participants performed recall and old/new recognition tests composed of targets, critical lures, and unrelated lures. HC exhibited higher true memories and better discriminability between true and false memory compared to SZ. High, versus low, associative strength increased false memory rates in both groups. However, explicit "relational processing" instructions positively improved true memory rates only in HC. Finally, true and false memory rates were associated with severity of disorganized and negative symptoms in SZ. These results suggest that reduced processing of semantic relationships during encoding in SZ may stem from an inability to implement explicit relational processing strategies rather than a fundamental deficit in the implicit activation and retrieval of word meanings from patients' semantic lexicon.
View details for DOI 10.1016/j.schres.2013.04.007
View details for Web of Science ID 000320598700017
View details for PubMedID 23623175
Abnormal Activity-Dependent Brain Lactate and Glutamate plus Glutamine Responses in Panic Disorder
2013; 73 (11): 1111-1119
Prior evidence suggests panic disorder (PD) is characterized by neurometabolic abnormalities, including increased brain lactate responses to neural activation. Increased lactate responses could reflect a general upregulation of metabolic responses to neural activation. However, prior studies in PD have not measured activity-dependent changes in brain metabolites other than lactate. Here we examine activity-dependent changes in both lactate and glutamate plus glutamine (glx) in PD.Twenty-one PD patients (13 remitted, 8 symptomatic) and 12 healthy volunteers were studied. A single-voxel, J-difference, magnetic resonance spectroscopy editing sequence was used to measure lactate and glx changes in visual cortex induced by visual stimulation.The PD patients had significantly greater activity-dependent increases in brain lactate than healthy volunteers. The differences were significant for both remitted and symptomatic PD patients, who did not differ from each other. Activity-dependent changes in glx were significantly smaller in PD patients than in healthy volunteers. The temporal correlation between lactate and glx changes was significantly stronger in control subjects than in PD patients.The novel demonstration that glx responses are diminished and temporally decoupled from lactate responses in PD contradicts the model of a general upregulation of activity-dependent brain metabolic responses in PD. The increase in activity-dependent brain lactate accumulation appears to be a trait feature of PD. Given the close relationship between lactate and pH in the brain, the findings are consistent with a model of brain metabolic and pH dysregulation associated with altered function of acid-sensitive fear circuits contributing to trait vulnerability in PD.
View details for DOI 10.1016/j.biopsych.2012.12.015
View details for Web of Science ID 000318997000013
View details for PubMedID 23332354
Oxytocin and Vasopressin in Children and Adolescents With Autism Spectrum Disorders: Sex Differences and Associations With Symptoms
2013; 6 (2): 91-102
There has been intensified interest in the neuropeptides oxytocin (OT) and arginine vasopressin (AVP) in autism spectrum disorders (ASD) given their role in affiliative and social behavior in animals, positive results of treatment studies using OT, and findings that genetic polymorphisms in the AVP-OT pathway are present in individuals with ASD. Nearly all such studies in humans have focused only on males. With this preliminary study, we provide basic and novel information on the involvement of OT and AVP in autism, with an investigation of blood plasma levels of these neuropeptides in 75 preadolescent and adolescent girls and boys ages 8-18: 40 with high-functioning ASD (19 girls, 21 boys) and 35 typically developing children (16 girls, 19 boys). We related neuropeptide levels to social, language, repetitive behavior, and internalizing symptom measures in these individuals. There were significant gender effects: Girls showed higher levels of OT, while boys had significantly higher levels of AVP. There were no significant effects of diagnosis on OT or AVP. Higher OT values were associated with greater anxiety in all girls, and with better pragmatic language in all boys and girls. AVP levels were positively associated with restricted and repetitive behaviors in girls with ASD but negatively (nonsignificantly) associated with these behaviors in boys with ASD. Our results challenge the prevailing view that plasma OT levels are lower in individuals with ASD, and suggest that there are distinct and sexually dimorphic mechanisms of action for OT and AVP underlying anxiety and repetitive behaviors. Autism Res 2013, 6: 91-102. © 2013 International Society for Autism Research, Wiley Periodicals, Inc.
View details for DOI 10.1002/aur.1270
View details for Web of Science ID 000318117500003
View details for PubMedID 23413037
Windows to the soul: vision science as a tool for studying biological mechanisms of information processing deficits in schizophrenia
Frontiers in Psychology
View details for DOI 10.3389/fpsyg.2013.00681
Windows to the soul: vision science as a tool for studying biological mechanisms of information processing deficits in schizophrenia.
Frontiers in psychology
2013; 4: 681-?
Cognitive and information processing deficits are core features and important sources of disability in schizophrenia. Our understanding of the neural substrates of these deficits remains incomplete, in large part because the complexity of impairments in schizophrenia makes the identification of specific deficits very challenging. Vision science presents unique opportunities in this regard: many years of basic research have led to detailed characterization of relationships between structure and function in the early visual system and have produced sophisticated methods to quantify visual perception and characterize its neural substrates. We present a selective review of research that illustrates the opportunities for discovery provided by visual studies in schizophrenia. We highlight work that has been particularly effective in applying vision science methods to identify specific neural abnormalities underlying information processing deficits in schizophrenia. In addition, we describe studies that have utilized psychophysical experimental designs that mitigate generalized deficit confounds, thereby revealing specific visual impairments in schizophrenia. These studies contribute to accumulating evidence that early visual cortex is a useful experimental system for the study of local cortical circuit abnormalities in schizophrenia. The high degree of similarity across neocortical areas of neuronal subtypes and their patterns of connectivity suggests that insights obtained from the study of early visual cortex may be applicable to other brain regions. We conclude with a discussion of future studies that combine vision science and neuroimaging methods. These studies have the potential to address pressing questions in schizophrenia, including the dissociation of local circuit deficits vs. impairments in feedback modulation by cognitive processes such as spatial attention and working memory, and the relative contributions of glutamatergic and GABAergic deficits.
View details for DOI 10.3389/fpsyg.2013.00681
View details for PubMedID 24198792
View details for PubMedCentralID PMC3813897
Proactive and reactive cognitive control and dorsolateral prefrontal cortex dysfunction in first episode schizophrenia.
2013; 2: 590-599
Cognitive control deficits have been consistently documented in patients with schizophrenia. Recent work in cognitive neuroscience has hypothesized a distinction between two theoretically separable modes of cognitive control-reactive and proactive. However, it remains unclear the extent to which these processes are uniquely associated with dysfunctional neural recruitment in individuals with schizophrenia. This functional magnetic resonance imaging (fMRI) study utilized the color word Stroop task and AX Continuous Performance Task (AX-CPT) to tap reactive and proactive control processes, respectively, in a sample of 54 healthy controls and 43 patients with first episode schizophrenia. Healthy controls demonstrated robust dorsolateral prefrontal, anterior cingulate, and parietal cortex activity on both tasks. In contrast, patients with schizophrenia did not show any significant activation during proactive control, while showing activation similar to control subjects during reactive control. Critically, an interaction analysis showed that the degree to which prefrontal activity was reduced in patients versus controls depended on the type of control process engaged. Controls showed increased dorsolateral prefrontal cortex (DLPFC) and parietal activity in the proactive compared to the reactive control task, whereas patients with schizophrenia did not demonstrate this increase. Additionally, patients' DLPFC activity and performance during proactive control was associated with disorganization symptoms, while no reactive control measures showed this association. Proactive control processes and concomitant dysfunctional recruitment of DLPFC represent robust features of schizophrenia that are also directly associated with symptoms of disorganization.
View details for DOI 10.1016/j.nicl.2013.04.010
View details for PubMedID 24179809
Excessive contralateral motor overflow in schizophrenia measured by fMRI
2012; 202 (1): 38-45
Schizophrenia is characterized by significant problems in control of behavior; however, the disturbances in neural systems that control movement remain poorly characterized. We used functional magnetic resonance imaging (fMRI) to evaluate the origin of motor overflow in schizophrenia. Twenty-seven clinically stable medicated outpatients with Diagnostic and Statistical Manual, 4th edition, text revision (DSM-IV-TR)-defined schizophrenia (SZ), and 18 healthy control (HC) subjects, all right-handed, performed a dominant-handed, single-choice visual sensorimotor reaction time paradigm during fMRI. Voxel-wise analyses were conducted within sensorimotor cortical and striatal regions on general linear model (GLM)-derived measures of blood oxygen level-dependent (BOLD) signal change. The SZ group was not different from the HC group in reaction time, activation in somatosensory or motor cortices ipsilateral to the active (intended) descending corticospinal tract, nor visual cortex. However, in the right hemisphere (contralateral to the active M1), the SZ group showed significantly higher activation in primary motor cortex and adjacent premotor and somatosensory cortices (right Brodmann areas (BA) 1 through 4, and 6), and significantly lower activation in bilateral basal ganglia. Right BA 4 activation was strongly related to disorganization and poverty symptoms (and unrelated to medications) in the patient group. This study provides evidence in SZ of excessive neural activity in motor cortex contralateral to the intended primary motor cortex, which may form the basis for altered motor laterality and motor overflow previously observed, and disorganized behavior. This pathological motor overflow may be partly due to altered modulation of intended movement within the basal ganglia and premotor cortex.
View details for DOI 10.1016/j.pscychresns.2012.03.005
View details for Web of Science ID 000306622400005
View details for PubMedID 22608155
Automated classification of fMRI during cognitive control identifies more severely disorganized subjects with schizophrenia
2012; 135 (1-3): 28-33
The establishment of a neurobiologically based nosological system is one of the ultimate goals of modern biological psychiatry research. Developments in neuroimaging and statistical/machine learning have provided useful basic tools for these efforts. Recent studies have demonstrated the utility of fMRI as input data for the classification of schizophrenia, but none, to date, has used fMRI of cognitive control for this purpose. In this study, we evaluated the accuracy of an unbiased classification method on fMRI data from a large cohort of subjects with first episode schizophrenia and a cohort of age matched healthy control subjects while they completed the AX version of the Continuous Performance Task (AX-CPT). We compared these results to classifications based on AX-CPT behavioral data. Classification accuracy for DSM-IV defined schizophrenia using fMRI data was modest and comparable to classifications conducted with behavioral data. Interestingly fMRI classifications did however identify a distinct subgroup of patients with greater behavioral disorganization, whereas behavioral data classifications did not. These results suggest that fMRI-based classification could be a useful tool in defining a neurobiologically distinct subgroup within the clinically defined syndrome of schizophrenia, reflecting alterations in discrete neural circuits. Independent validation of classification-based phenotypes using other biological data such as genetics would provide a strong test of this hypothesis.
View details for DOI 10.1016/j.schres.2012.01.001
View details for Web of Science ID 000300940000005
View details for PubMedID 22277668
Neural correlates of relational and item-specific encoding during working and long-term memory in schizophrenia
2012; 59 (2): 1719-1726
Successful long-term memory (LTM) depends upon effective control of information in working memory (WM), and there is evidence that both WM and LTM are impaired by schizophrenia. This study tests the hypothesis that LTM deficits in schizophrenia may result from impaired control of relational processing in WM due to dorsolateral prefrontal cortex (DLPFC) dysfunction. fMRI was performed on 19 healthy controls and 20 patients with schizophrenia during WM tasks emphasizing relational (reorder trials) versus item-specific (rehearse trials) processing. WM activity was also examined with respect to LTM recognition on a task administered outside the scanner. Receiver operator characteristic analysis assessed familiarity and recollection components of LTM. Patients showed a disproportionate familiarity deficit for reorder versus rehearse trials against a background of generalized LTM impairments. Relational processing during WM led to DLPFC activation in both groups. However, this activation was less focal in patients than in controls, and patients with more severe negative symptoms showed less of a DLPFC increase. fMRI analysis of subsequent recognition performance revealed a group by condition interaction. High LTM for reorder versus rehearse trials was associated with bilateral DLPFC activation in controls, but not in patients who activated the left middle temporal and inferior occipital gyrus. Results indicate that although patients can activate the DLPFC on a structured relational WM task, this activation is less focal and does not translate to high retrieval success, suggesting a disruption in the interaction between WM and LTM processes in schizophrenia.
View details for DOI 10.1016/j.neuroimage.2011.08.055
View details for Web of Science ID 000298210600094
View details for PubMedID 21907293
From lumping to splitting and back again: Atypical social and language development in individuals with clinical-high-risk for psychosis, first episode schizophrenia, and autism spectrum disorders
2011; 131 (1-3): 146-151
Individuals with autism and schizophrenia exhibit atypical language and social symptoms. The extent to which these symptoms are evident during development and in current functioning is unclear.Three groups of patients aged 11-20 diagnosed as clinical-high-risk for psychosis (CHR; n=15), first episode psychosis (FEP; n=16), and autism spectrum disorders (ASD; n=20), plus typically developing individuals (TYP; n=20) were compared on common autism parent-report questionnaires assessing social and language development and current functioning including the Social Communication Questionnaire, the Children's Communication Checklist, and the Social Reciprocity Scale.All clinical groups demonstrated atypical social and language development, with social impairment highest in ASD. Twenty percent of participants with CHR and FEP met diagnostic criteria for ASD as assessed by parent-report. ASD exhibited greater current syntactic, and pragmatic language symptoms including delayed echolalia, pedantic speech, and deficits in appreciating irony and sarcasm. All clinical groups exhibited current deficits in social functioning. CHR and FE had similar and intermediate levels of functioning relative to ASD and TYP, with CHR generally scoring closer to TYP, providing construct validity for the CHR diagnostic label.The results of this study suggest that ASDs, CHR, and FEP share common features of atypical neurodevelopment of language and social function. Evidence of impaired social reciprocity across both disorders and distinct language symptoms in ASDs provides important information for differential diagnosis and psychosis prevention, as well as leads for future investigations of comparative genetics and pathophysiology.
View details for DOI 10.1016/j.schres.2011.03.005
View details for Web of Science ID 000295111400024
View details for PubMedID 21458242
General and Specific Functional Connectivity Disturbances in First-Episode Schizophrenia During Cognitive Control Performance
2011; 70 (1): 64-72
Cognitive control impairments in schizophrenia are thought to arise from dysfunction of interconnected networks of brain regions, but interrogating the functional dynamics of large-scale brain networks during cognitive task performance has proved difficult. We used functional magnetic resonance imaging to generate event-related whole-brain functional connectivity networks in participants with first-episode schizophrenia and healthy control subjects performing a cognitive control task.Functional connectivity during cognitive control performance was assessed between each pair of 78 brain regions in 23 patients and 25 control subjects. Network properties examined were region-wise connectivity, edge-wise connectivity, global path length, clustering, small-worldness, global efficiency, and local efficiency.Patients showed widespread functional connectivity deficits in a large-scale network of brain regions, which primarily affected connectivity between frontal cortex and posterior regions and occurred irrespective of task context. A more circumscribed and task-specific connectivity impairment in frontoparietal systems related to cognitive control was also apparent. Global properties of network topology in patients were relatively intact.The first episode of schizophrenia is associated with a generalized connectivity impairment affecting most brain regions but that is particularly pronounced for frontal cortex. Superimposed on this generalized deficit, patients show more specific cognitive-control-related functional connectivity reductions in frontoparietal regions. These connectivity deficits occur in the context of relatively preserved global network organization.
View details for DOI 10.1016/j.biopsych.2011.02.019
View details for Web of Science ID 000291559300013
View details for PubMedID 21514570
Modafinil modulation of the default mode network
2011; 215 (1): 23-31
The default mode network (DMN) is a functional network which is implicated in a range of cognitive processes. This network is proposed to consist of hubs located in the ventromedial prefrontal cortex (vmPFC), posterior cingulate/retrosplenial cortex (PCC/rSpl), and inferior parietal lobule (IPL), with other midline cortical and temporal lobe nodes connected to these hubs. How this network is modulated by neurochemical systems during functional brain activity is not yet understood.In the present study, we used the norepinephrine/dopamine transporter inhibitor modafinil to test the hypothesis that this drug modulates the DMN.Eighteen healthy right-handed adults participated in a double-blind, placebo-controlled study of single oral dose modafinil 200 mg. They performed a simple visual sensorimotor task during slow event-related fMRI. Drug effects were interrogated within the DMN defined by task-induced deactivation (TID) on placebo.There was a trend toward faster reaction time (RT) on modafinil (Cohen's d = 0.38). Brain regions within the DMN which exhibited significant modafinil-induced augmentation of TID included vmPFC, PCC/rSpl, and left IPL. Across subjects, the modafinil effect on TID in the vmPFC was significantly and specifically associated with drug effects on RT speeding.Modafinil augments TID in the DMN to facilitate sensorimotor processing speed, an effect which may be particularly dependent on changes in vmPFC activity. This is consistent with the gain control function of catecholamine systems and may represent an important aspect of the pro-cognitive effects of modafinil.
View details for DOI 10.1007/s00213-010-2111-5
View details for Web of Science ID 000289293000003
View details for PubMedID 21153806
Prefrontal Cortical Deficits and Impaired Cognition-Emotion Interactions in Schizophrenia
AMERICAN JOURNAL OF PSYCHIATRY
2011; 168 (3): 276-285
Despite schizophrenia patients' reports of diminished experience of emotion in interviews and self-report measures, their emotional experience in the presence of emotional stimuli and in daily life ("in the moment") appears largely intact. To examine emotion-cognition interactions, the authors tested the hypothesis that schizophrenia patients have unimpaired in-the-moment emotional reactivity but have a deficit in prefrontal cortical mechanisms needed to maintain and report on experience following exposure to emotional stimuli.Using a slow event-related functional MRI paradigm, the authors examined the brain activity of 23 schizophrenia patients and 24 healthy comparison subjects during trials in which they viewed an affective picture and, after a delay, reported their emotional experience while viewing it.The patients' self-reports of emotional experience differed from those of the healthy subjects when they rated their experience on dimensions inconsistent with the stimulus valence but not when the dimension was consistent with it. In the presence of emotional stimuli, brain activity in the patients was similar to that of the comparison subjects. During the delay, however, patients showed decreased activation in a network of brain structures, including the dorsolateral prefrontal cortex and other prefrontal, limbic, and paralimbic areas. In patients, the delay-related response of the dorsolateral prefrontal cortex to pleasant stimuli correlated negatively with an anhedonia measure.These results suggest that schizophrenia is characterized by a failure of prefrontal circuitry supporting the link between emotion and goal-directed behavior and that the failure of this mechanism may contribute to deficits in processes related to emotion-cognition interaction.
View details for DOI 10.1176/appi.ajp.2010.09081215
View details for Web of Science ID 000287916900011
View details for PubMedID 21205806
An Index of Relative Central alpha-Adrenergic Receptor Antagonism by Antipsychotic Medications
EXPERIMENTAL AND CLINICAL PSYCHOPHARMACOLOGY
2011; 19 (1): 31-39
Antipsychotic medications exert variable and clinically significant levels of antagonism at central α-adrenergic receptors. To evaluate the impact of this activity on both clinical and experimental measures, an index estimating the relative activity of these medications is needed. We comprehensively searched the empirical literature testing in vitro binding to mammalian brain α-adrenergic receptors of all antipsychotic medications available for clinical use in the United States as of August 2010 and created a quantitative summary index of the potency of binding to α receptors relative to haloperidol (HALα1 and HALα2 equivalents). The potency of binding at α1- and α2-adrenergic receptors varies widely among these medications, with a 532-fold range for α1 antagonism and a 400-fold range for α2 antagonism among atypical antipsychotics. There is considerable overlap between atypical and typical antipsychotic medication groups on each of these measures. This index of HALα equivalents should facilitate the determination of the effects of α-adrenergic antagonism by these medications on clinical efficacy, side effects, and biological and cognitive measures of illness and treatment.
View details for DOI 10.1037/a0022258
View details for Web of Science ID 000287466000004
View details for PubMedID 21341921
- Broader orientation tuning in patients with schizophrenia Frontiers in Human Neuroscience 2011
Gamma Oscillatory Power is Impaired During Cognitive Control Independent of Medication Status in First-Episode Schizophrenia
2010; 35 (13): 2590-2599
Schizophrenia is characterized by impaired cognitive control associated with prefrontal cortex dysfunction, but the underlying pathophysiological mechanisms remain unknown. Higher cognitive processes are associated with cortical oscillations in the gamma range, which are also impaired in chronic schizophrenia. We tested whether cognitive control-related gamma deficits are observed in first-episode patients, and whether they are associated with antipsychotic medication exposure. Fifty-three first-episode schizophrenia patients (21 without antipsychotic medication treatment) and 29 healthy control subjects underwent electroencephalography (EEG) during performance of a preparatory cognitive control task (preparing to overcome prepotency or POP task). The first-episode schizophrenia patient group was impaired (relative to the control group) on task performance and on delay-period gamma power at each of the three subgroups of frontal electrodes. The unmedicated patient subgroup was similarly impaired compared with controls, and was not different on these measures compared with the medicated patient subgroup. In contrast, delay-period theta power was not impaired in the full patient group nor in the unmedicated patient subgroup. Impaired cognitive control-related gamma cortical oscillatory activity is present at the first psychotic episode in schizophrenia, and is independent of medication status. This suggests that altered local circuit function supporting high-frequency oscillatory activity in prefrontal cortex ensembles may serve as the pathophysiological substrate of cognitive control deficits in schizophrenia.
View details for DOI 10.1038/npp.2010.150
View details for Web of Science ID 000284104400011
View details for PubMedID 20827271
Use of Eye Movement Monitoring to Examine Item and Relational Memory in Schizophrenia
2010; 68 (7): 610-616
Patients with schizophrenia may be impaired at remembering interitem and item-context relationships (relational memory), even when memory for items is intact. Here, we applied the novel approach of using eye movements to assess integrity of item and relational memory in schizophrenia. This method does not rely on introspection and may be more readily translated to animal models than traditional behavioral methods.Sixteen healthy control subjects and 16 patients were administered a scene memory task while eye movements were monitored. During testing, participants indicated whether the scenes were unchanged, contained a new item (item manipulation), had a change in item location (relational manipulation), or were new. It was predicted that memory would be disproportionately impaired when relational changes were made.Results confirmed that tasks were equally difficult and showed that patients were impaired identifying all scene types. These behavioral impairments were associated with more severe disorganization and negative symptoms. Eye movement results were more specific. Both groups looked disproportionately at critical regions of repeated versus novel scenes-an effect of scene repetition. However, in contrast with predictions, patients showed equivalent eye-movement-based memory impairment whether changes were relational or item-based.This is the first experiment to demonstrate that eye movements can be used to investigate item and relational memory in schizophrenia. The eye movement procedure was well tolerated and was more specific than behavioral measures with respect to memory impairment. Results suggest that eye movements may be of use in clinical trials and translational studies employing animal models.
View details for DOI 10.1016/j.biopsych.2010.06.001
View details for Web of Science ID 000282356900005
View details for PubMedID 20673874
- Response to Comment on "Modafinil Shifts Human Locus Coeruleus to Low-Tonic, High-Phasic Activity During Functional MRI" SCIENCE 2010; 328 (5976)
GABA Concentration Is Reduced in Visual Cortex in Schizophrenia and Correlates with Orientation-Specific Surround Suppression
JOURNAL OF NEUROSCIENCE
2010; 30 (10): 3777-3781
The neural mechanisms underlying cognitive deficits in schizophrenia remain essentially unknown. The GABA hypothesis proposes that reduced neuronal GABA concentration and neurotransmission results in cognitive impairments in schizophrenia. However, few in vivo studies have directly examined this hypothesis. We used magnetic resonance spectroscopy (MRS) at high field to measure visual cortical GABA levels in 13 subjects with schizophrenia and 13 demographically matched healthy control subjects. We found that the schizophrenia group had an approximately 10% reduction in GABA concentration. We further tested the GABA hypothesis by examining the relationship between visual cortical GABA levels and orientation-specific surround suppression (OSSS), a behavioral measure of visual inhibition thought to be dependent on GABAergic synaptic transmission. Previous work has shown that subjects with schizophrenia exhibit reduced OSSS of contrast discrimination (Yoon et al., 2009). For subjects with both MRS and OSSS data (n = 16), we found a highly significant positive correlation (r = 0.76) between these variables. GABA concentration was not correlated with overall contrast discrimination performance for stimuli without a surround (r = -0.10). These results suggest that a neocortical GABA deficit in subjects with schizophrenia leads to impaired cortical inhibition and that GABAergic synaptic transmission in visual cortex plays a critical role in OSSS.
View details for DOI 10.1523/JNEUROSCI.6158-09.2010
View details for Web of Science ID 000275400000025
View details for PubMedID 20220012
Perception Measurement in Clinical Trials of Schizophrenia: Promising Paradigms From CNTRICS
2009; 35 (1): 163-181
The third meeting of the Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia (CNTRICS) focused on selecting promising measures for each of the cognitive constructs selected in the first CNTRICS meeting. In the domain of perception, the 2 constructs of interest were gain control and visual integration. CNTRICS received 5 task nominations for gain control and three task nominations for visual integration. The breakout group for perception evaluated the degree to which each of these tasks met prespecified criteria. For gain control, the breakout group for perception believed that 2 of the tasks (prepulse inhibition of startle and mismatch negativity) were already mature and in the process of being incorporated into multisite clinical trials. However, the breakout group recommended that steady-state visual-evoked potentials be combined with contrast sensitivity to magnocellular vs parvocellular biased stimuli and that this combined task and the contrast-contrast effect task be recommended for translation for use in clinical trial contexts in schizophrenia research. For visual integration, the breakout group recommended the Contour Integration and Coherent Motion tasks for translation for use in clinical trials. This manuscript describes the ways in which each of these tasks met the criteria used by the breakout group to evaluate and recommend tasks for further development.
View details for DOI 10.1093/schbul/sbn156
View details for Web of Science ID 000261682700018
View details for PubMedID 19023123
- Diminished orientation-specific contextual modulation of visual processing in schizophrenia Schizophrenia Bulletin 2009; 35 (6): 1078-84
Association of dorsolateral prefrontal cortex dysfunction with disrupted coordinated brain activity in schizophrenia: Relationship with impaired cognition, behavioral disorganization, and global function
11th International Congress on Schizophrenia Research/8th Biennial Mt Sinai Conference on Cognition in Schizophrenia
AMER PSYCHIATRIC PUBLISHING, INC. 2008: 1006–14
Although deficits in cognitive control are thought to contribute to the diverse cognitive and behavioral abnormalities in individuals with schizophrenia, the neural mechanisms underlying these deficits remain unclear. In this event-related functional magnetic resonance imaging (fMRI) study, the authors tested the hypothesis that during cognitive control tasks, impaired activation of the dorsolateral prefrontal cortex in schizophrenia patients is associated with disrupted coordinated activity between this prefrontal region and a distributed brain network that supports cognitive control.Through the use of an event-related design, 25 patients with first-episode schizophrenia and 24 healthy comparison subjects, matched on demographic characteristics, were assessed while performing a version of the AX continuous performance task. Functional neuroimaging data were analyzed using 1) univariate (region-of-interest blood-oxygen-level-dependent [BOLD] time series and whole brain voxel-wise regression) analysis to confirm the presence of dorsolateral prefrontal cortex dysfunction and 2) multivariate analysis to examine dorsolateral prefrontal cortex functional connectivity. In addition, correlations between dorsolateral prefrontal cortex functional connectivity and the following variables were investigated: clinical symptoms, task performance, and coordinated brain activity associated with cognitive control.Schizophrenia patients exhibited a specific deficit in cognitive control, with significantly reduced accuracy in the BX condition relative to any other condition. Univariate fMRI revealed dorsolateral prefrontal cortex dysfunction during the high cognitive control condition. Multivariate analysis revealed significant impairment in functional connectivity between the dorsolateral prefrontal cortex and task-relevant brain regions. Significant correlations were also found between dorsolateral prefrontal cortex functional connectivity and cognitive performance, behavioral disorganization, and global functioning.These findings suggest that there is an association between decreased dorsolateral prefrontal cortex activity and connectivity and a task-related neural network. This deficit in coordinated brain activity may result in the disabling disorganization symptoms related to impaired cognition in individuals with schizophrenia.
View details for DOI 10.1176/appi.ajp.2008.07060945
View details for Web of Science ID 000258113700015
View details for PubMedID 18519527
- Multivariate Pattern Analysis of fMRI Data Reveals Deficits in Distributed Representations in Schizophrenia Biological Psychiatry 2008; 64 (12)
- Modafinil Shifts Human Locus Coeruleus to Low-Tonic, High-Phasic Activity During Functional MRI Science 2008; 322 (5908)
Segregation of function in the lateral prefrontal cortex during visual object working memory
2007; 1184: 217-225
Working memory is a set of cognitive operations facilitating higher order cognition and complex behavior. A particularly important aspect of working memory is the linkage of past sensory events to planned actions. While the lateral prefrontal cortex has been proposed to serve this temporal integrative function, the precise mapping of specific components of this process within the lateral prefrontal cortex has yet to be clarified. In this human fMRI experiment, we employed a paradigm that segregates retrospective sensory maintenance from prospective action planning processes. Our results suggest that the ventrolateral PFC supports retrospective sensory representations while the dorsolateral PFC supports prospective action representations.
View details for DOI 10.1016/j.brainres.2007.09.074
View details for Web of Science ID 000252096600025
View details for PubMedID 17980353
- Neuroimaging of cognitive disability in schizophrenia: Search for a pathophysiological mechanism INTERNATIONAL REVIEW OF PSYCHIATRY 2007; 19 (4): 419-429
Preserved function of the fusiform face area in schizophrenia as revealed by fMRI
2006; 148 (2-3): 205-216
Many lines of evidence suggest that individuals with schizophrenia suffer from face processing deficits. However, the specificity of these deficits and the neural dysfunction underlying them remain unclear. To address these questions, we evaluated the functional status of a critical region for face processing, the fusiform face area (FFA), in subjects with schizophrenia. Fourteen schizophrenia patients and 10 healthy control subjects participated in an fMRI experiment to determine the functional status of the FFA by viewing a series of faces and exemplars of other object categories, while completing a low-level task designed to verify their engagement with the stimuli. Behavioral performance and activation of the FFA were equivalent between groups. Thirteen of 14 patients and all control subjects displayed FFA activation. Furthermore, the degree of FFA activation, as measured by FFA volume and magnitude of activity, was similar between groups. The FFA, a critical region in the neural system subserving the perceptual processing of faces, appears to be intact in schizophrenia. These results call into question the presence of a specific face processing deficit in schizophrenia.
View details for DOI 10.1016/j.pscychresns.2006.06.002
View details for Web of Science ID 000242885800013
View details for PubMedID 17095198
Differential effects of distraction during working memory on delay-period activity in the prefrontal cortex and the visual association cortex
2006; 29 (4): 1117-1126
Maintaining relevant information for later use is a critical aspect of working memory (WM). The lateral prefrontal cortex (PFC) and posterior sensory cortical areas appear to be important in supporting maintenance. However, the relative and unique contributions of these areas remain unclear. We have designed a WM paradigm with distraction to probe the contents of maintenance representations in these regions. During delayed recognition trials of faces, selective interference was evident behaviorally with face distraction leading to significantly worse performance than with scene distraction. Event-related fMRI of the human brain showed that maintenance activity in the lateral PFC, but not in visual association cortex (VAC), was selectively disrupted by face distraction. Additionally, the functional connectivity between the lateral PFC and the VAC was perturbed during these trials. We propose a hierarchical and distributed model of active maintenance in which the lateral PFC codes for abstracted mnemonic information, while sensory areas represent specific features of the memoranda. Furthermore, persistent coactivation between the PFC and sensory areas may be a mechanism by which information is actively maintained.
View details for DOI 10.1016/j.neuroimage.2005.08.024
View details for Web of Science ID 000235534400009
View details for PubMedID 16226895