Reduced Dorsal Prefrontal Gray Matter After Chronic Ketamine Use

doi:10.1016/j.biopsych.2010.08.030

Biological Psychiatry

Volume 69, Issue 1, 1 January 2011, Pages 42-48

https://doi.org/10.1016/j.biopsych.2010.08.030 Get rights and content

Background

Use of ketamine as a recreational drug is spreading rapidly among young people all over the world. Epidemiological studies have linked chronic ketamine use with a number of problems, including cognitive impairments, bladder dysfunction, and ketamine-related death. However, little is known about the long-term effects of ketamine use on brain structure and function.

Methods

We used voxel based morphometry in conjunction with statistical parametric mapping on the structural magnetic resonance images of ketamine-dependent (n = 41) and drug-naive control individuals (n = 44) to assess differences in gray matter volume between the two groups.

Results

We observed significant decreases in gray matter volume in bilateral frontal cortex (left superior frontal gyrus and right middle frontal gyrus) of ketamine users in comparison with control subjects (p < .05 corrected for multiple comparisons at cluster-level). Duration of ketamine use was negatively correlated with gray matter volume in bilateral frontal cortex, whereas the estimated total lifetime ketamine consumption was negatively correlated with gray matter volume in left superior frontal gyrus.

Conclusions

We have demonstrated a reduction in frontal gray matter volume in patients after chronic ketamine use. The link between frontal gray matter attenuation and the duration of ketamine use and cumulative doses of ketamine perhaps suggests a dose-dependent effect of long-term use of the drug. Our results have important connotations for the clinical picture that is likely to emerge with the growing recreational use of ketamine and is also relevant to the status of the drug as a model for schizophrenia.

Section snippets

Subjects

Eight to five subjects (41 ketamine-dependent participants and 44 age-matched healthy volunteers) participated in this study. Ketamine-dependent volunteers were recruited from two drug rehabilitation centers: the Kangda Voluntary Drug Rehabilitation Centers in Hunan Province and the Department of Addiction Medicine, Hunan Brain Hospital. All these subjects met the DSM-IV criteria for lifetime ketamine dependence determined from the Structured Clinical Interview (21). Subjects were excluded if

Demographic Data

Groups were age- and gender-matched, although there was a difference in educational levels (p < .01). The ketamine-dependent subjects consumed ketamine solely by snorting ketamine powder. A number of symptoms were found in the ketamine group but not the control group: bladder dysfunction (four participants), chronic gastritis (seven participants), and chronic hepatitis B (one participant). Participants gave the following reasons for using ketamine: dealing with intensive family pressure (5

Discussion

To our knowledge, the current study provides unique VBM data demonstrating gray matter differences between chronic ketamine users and matched control subjects. Ketamine use was associated with reduced gray matter volumes in two areas: the left superior frontal gyrus, and right middle frontal gyrus. Reductions in gray matter volume in both regions was correlated with the duration of ketamine use, and the reduction in left superior frontal gyrus volume was correlated with estimated total lifetime

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Proteomic Characteristics of the Prefrontal Cortex and Hippocampus in Mice with Chronic Ketamine-Induced Anxiety and Cognitive Impairment
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Schizophrenia, a complex psychiatric disorder with diverse symptoms, has been linked to ketamine, known for its N-methyl-D-aspartate (NMDA) receptor antagonistic properties. Understanding the distinct roles and mechanisms of ketamine is crucial, especially regarding its induction of schizophrenia-like symptoms. Recent research highlights the impact of ketamine on key brain regions associated with schizophrenia, specifically the prefrontal cortex (PFC) and hippocampus (Hip). This study focused on these regions to explore proteomic changes related to anxiety and cognitive impairment in a chronic ketamine-induced mouse model of schizophrenia. After twelve consecutive days of ketamine administration, brain tissues from these regions were dissected and analyzed. Using tandem mass tag (TMT) labeling quantitative proteomics techniques, 34,797 and 46,740 peptides were identified in PFC and Hip, corresponding to 5,668 and 6,463 proteins, respectively. In the PFC, a total of 113 proteins showed differential expression, primarily associated with the immuno-inflammatory process, calmodulin, postsynaptic density protein, and mitochondrial function. In the Hip, 129 differentially expressed proteins were screened, mainly related to synaptic plasticity proteins and mitochondrial respiratory chain complex-associated proteins. Additionally, we investigated key proteins within the glutamatergic synapse pathway and observed decreased expression levels of phosphorylated CaMKII and CREB. Overall, the study unveiled a significant proteomic signature in the chronic ketamine-induced schizophrenia mouse model, characterized by anxiety and cognitive impairment in both the PFC and Hip, and this comprehensive proteomic dataset may not only enhance our understanding of the molecular mechanisms underlying ketamine-related mental disorders but also offer valuable insights for future disease treatments.
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We recently demonstrated that patients with ketamine dependence (KD) have increased serum levels of neurofilament light chain (NfL), a novel marker of active neuroaxonal pathology, with NfL levels being significantly higher in those KD patients comorbid with major depressive disorder (MDD). However, considering that NfL elevation has been associated with both ketamine-related brain pathology and MDD, we could not determine whether the observed elevation of NfL levels was driven by an interaction of KD with MDD or by MDD itself. Therefore, we compared serum NfL levels between 35 patients with MDD without ketamine use (MDD group), 23 with KD without MDD (KD without MDD group), 30 KD with MDD (KD with MDD group), and 86 healthy controls (HC group). Using a 2*2 (KD*MDD) generalized linear model controlling for age, sex, body mass index, and smoking status, we found that KD and KD*MDD interactions, but not MDD factor, significantly affected NfL levels. Posthoc tests showed that the KD with MDD group had significantly higher NfL levels than all other groups. The KD without MDD group also showed higher NfL levels than the MDD and, as shown before, HC groups. The levels in MDD group were not different from the HC group. These results suggest that the interaction of KD with MDD, but not MDD alone, results in increased vulnerability to neuroaxonal pathology.
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Ketamine has become a major substance of abuse worldwide. Nevertheless, The long-term effects of ketamine use on intrinsic spontaneous neural activity remain unknown.
In the present study, rs-fMRI was used to explore whether chronic ketamine use changes the intrinsic spontaneous neural activity, and whether the intrinsic spontaneous neural activity changes in chronic ketamine users(CKUs) are associated with cognitive impairments observed in chronic ketamine users.
28 CKUs and 30 healthy controls(HC) were enrolled. The fractional amplitude of low-frequency fluctuations (fALFF) was measured to evaluate the intrinsic spontaneous neural activity in multiple brain regions. Cognitive alterations were assessed using MATRICS Consensus Cognitive Battery (MCCB).
CKUs showed higher fALFF in the right parahippocampal gyrus(PHG), right anterior cingulate cortex(ACC), left cerebellar vermis, left posterior cingulate cortex(PCC), bilateral caudate, and lower fALFF in the right middle occipital gyrus(MOG), left cuneus, right precuneus. The fALFF in the right PHG, left cerebellar vermis, bilateral caudate, right ACC of CKUs presented a negative correlation with the average quantity of ketamine use/day(g) and estimated total ketamine consumption. The fALFF in left PCC had a negative correlation with the average quantity of ketamine use/day(g). Speed of processing on MCCB presented a negative correlation with the fALFF in the right MOG.
Our study found abnormal fALFF in multiple brain areas in CKUs, which indicated the changes of intrinsic spontaneous neural activity in multiple brain areas. The changes of fALFF were associated with the severity of ketamine use and cognitive impairment in CKUs.
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Chronic refractory cough significantly impairs the psychological and social aspects of quality of life. Loss of inhibitory control is suggested as a potential central neurobiological mechanism underlying chronic refractory cough.
Do structural and functional changes related to chronic cough occur in higher cortical brain regions?
The structural and resting-state functional alterations in the brains of 15 patients with chronic refractory cough and 15 age- and sex-matched healthy control participants were evaluated. Gray matter volumes of the whole brain were measured using voxel-based morphometry based on T1-weighted MRI. Intrinsic functional connectivity within large-scale brain networks was examined on resting-state functional MRI. Correlation analyses were performed to examine the relationships of these brain changes with duration, severity, and impact of cough.
Compared with healthy control participants, patients with chronic refractory cough demonstrated a lower gray matter volume in the left frontal cluster and enhanced functional connectivity within the left frontoparietal network, which were associated with greater cough scores. Furthermore, enhanced functional connectivity within the left frontoparietal network was associated with a greater psychological and social impact of coughing. Lower left frontal gray matter volume was associated with longer cough duration.
Structural and functional alterations in the left frontal brain regions may be implicated in the psychological and social impact and disease duration of chronic refractory cough. Our findings provide new perspectives on developing interventional approaches targeting the cognitive modulation of chronic coughing.
Ketamine use disorder: preclinical, clinical, and neuroimaging evidence to support proposed mechanisms of actions
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Ketamine, a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, has been exclusively used as an anesthetic in medicine and has led to new insights into the pathophysiology of neuropsychiatric disorders. Clinical studies have shown that low subanesthetic doses of ketamine produce antidepressant effects for individuals with depression. However, its use as a treatment for psychiatric disorders has been limited due to its reinforcing effects and high potential for diversion and misuse. Preclinical studies have focused on understanding the molecular mechanisms underlying ketamine's antidepressant effects, but a precise mechanism had yet to be elucidated. Here we review different hypotheses for ketamine's mechanism of action including the direct inhibition and disinhibition of NMDA receptors, aminomethylphosphonic acid receptors (AMPAR) activation, and heightened activation of monoaminergic systems. The proposed mechanisms are not mutually exclusive, and their combined influence may exert the observed structural and functional neural impairments. Long term use of ketamine induces brain structural, functional impairments, and neurodevelopmental effects in both rodents and humans. Its misuse has increased rapidly in the past 20 years and is one of the most common addictive drugs used in Asia. The proposed mechanisms of action and supporting neuroimaging data allow for the development of tools to identify ‘biotypes’ of ketamine use disorder (KUD) using machine learning approaches, which could inform intervention and treatment.
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Citation Excerpt :
The trend or marginal level of gray matter reductions in the MA are noteworthy, as this could implicate a trend of neuropathology toward psychosis development. We had previously reported ketamine chronic users showed gray matter reduced in the frontal cortex, specifically in the superior and middle frontal gyrus (Liao et al., 2011). The frontal cortical reductions were also found to be associated with total lifetime consumption of ketamine (Liao et al., 2011).
Methamphetamine (MA)-associated psychosis has become a public concern. However, its mechanism is not clear. Investigating similarities and differences between MA-associated psychosis and schizophrenia in brain alterations would be informative for neuropathology.
This study compared gray matter volumes of the brain across four participant groups: healthy controls (HC, n = 53), MA users without psychosis (MA, n = 22), patients with MA-associated psychosis (MAP, n = 34) and patients with schizophrenia (SCZ, n = 33). Clinical predictors of brain alterations, as well as association of brain alterations with psychotic symptoms and attention impairment were further investigated.
Compared with the HC, the MAP and the SCZ showed similar gray matter reductions in the frontal cortex, particularly in prefrontal areas. Moreover, a stepwise extension of gray matter reductions was exhibited across the MA – MAP – SCZ. Duration of abstinence was associated with regional volumetric recovery in the MAP, while this amendment in brain morphometry was not accompanied with symptom’s remission. Illness duration of psychosis was among the predictive factors of regional gray matter reductions in both psychotic groups. Volume reductions were found to be associated with attention impairment in the SCZ, while this association was reversed in the MAP in frontal cortex.
This study suggested MA-associated psychosis and schizophrenia had common neuropathology in cognitive-related frontal cortices. A continuum of neuropathology between MA use and schizophrenia was tentatively implicated. Illness progressions and glial repairments could both play roles in neuropathological changes in MA-associated psychosis.

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Archival ReportReduced Dorsal Prefrontal Gray Matter After Chronic Ketamine Use

Background

Methods

Results

Conclusions

Section snippets

Subjects

Demographic Data

Discussion

Forensic Sci Int

Int J Drug Policy

Neuropsychopharmacology

Neuroimage

Schizophr Res

Neuroimage

Neuroimage

Neuroimage

Trends Neurosci

Pharmacol Biochem Behav

Trends Cogn Sci

Eur Neuropsychopharmacol

Brain Res Bull

Schizophr Res

Neurosci Biobehav Rev

Conscious Cogn

J Psychiatr Res

Drug Alcohol Depend

Drug Alcohol Depend

Biol Psychiatry

Biol Psychiatry

Pharmacol Biochem Behav

Brain Cogn

Drug Alcohol Depend

Schizophr Res

Dinosaur girls, candy girls, and Trinity: Voices of Taiwanese club drug users

J Ethn Subst Abus

Sit Down to float: The cultural meaning of ketamine use in Hong Kong

Addict Res Theory

Recent trends in drug abuse in China

Acta Pharmacol Sin

5-Year trends in use of hallucinogens and other adjunct drugs among UK dance drug users

Eur Addict Res

Consequences of chronic ketamine self-administration upon neurocognitive function and psychological wellbeing: A 1-year longitudinal study

Addiction

Ketamine-associated bladder dysfunction

Int J Urol

Archival Report
Reduced Dorsal Prefrontal Gray Matter After Chronic Ketamine Use