Augmenting the understanding of the temporal experience of emotion by including other measures, such as a behavioral measure of anticipatory and consummatory pleasure, is an important next step . This study extends our understanding of one aspect of the emotion deficits observed in schizophrenia — deficits in anticipatory pleasure — to those early in the course of the illness. A related emotion deficit thathas been observed in samples of more chronically ill people with schizophrenia is the ability to maintain emotion experience . Ursu et al. found that emotion maintenance, specifically viewing an emotionally evocative picture and reporting emotion experience after a delay, was associated with diminished dorsolateral prefrontal cortex activation among people with schizophrenia. This suggests that emotion maintenance relies upon neural processes that not only support emotion but also cognitive control processes. Anticipation likely recruits similar brain regions, as anticipation requires a host of similar cognitive operations, such as creating and maintaining visual images and accessing “mental time travel” processes. While we did not include any neuropsychological measures or fMRI in our study, future studies may wish to include these measures to help answer such questions as a) whether people early in the course of a schizophrenia spectrum disorder also experience difficulties in emotion maintenance and b) whether similar brain regions are involved in both emotion anticipation and maintenance. There has been some preliminary work showing that directly targeting anticipatory deficits in treatment is related to increases in self-reported anticipatory pleasure on the TEPS .
Treating anticipatory deficits in newly diagnosed people with a schizophrenia spectrum disorder may be a particularly important time period for administering such interventions,vertical farm systems as it is before deficits in anticipatory pleasure are related to functioning but after such deficits are correlated with negative symptoms. An interesting yet unexplored question is whether an intervention targeting anticipatory deficits during the early stages of the illness would not only increase self-reported anticipatory pleasure, but whether the intervention would also be related to improved functional outcome or negative symptomatology over time. In summary, people with a recent-onset schizophrenia spectrum diagnosis reported lower levels of trait anticipatory pleasure but not consummatory pleasure on the TEPS when compared to a healthy control group. During the early stage of the illness, both anticipatory and consummatory pleasure scores appear to be related to negative symptom measures, but not to functional outcome measures. Future studies should continue to examine when anticipatory deficits emerge in schizophrenia, when such deficits relate to both symptoms and outcome measures, whether there are other individual differences that may account for such differences, and whether directly targeting anticipatory deficits in the early course of the illness would improve functional outcome or symptom severity as the illness progresses.Drug addiction is characterized by dysfunction in corticolimbic networks sub-serving attentional, emotional, and inhibitory processes . Insights into these systems-level deficits have been primarily advanced through in vivo, non-invasive brain imaging methodologies, such as functional magnetic resonance imaging . Increasingly, these methods are being used to examine resting-state functional connectivity , a measure of intrinsic activity that provides information on network-level function and its disruption in neuropsychiatric disorders , including substance use disorders .
Although the neurochemical bases of RSFC differences between addicted individuals and healthy controls are presently unclear, evidence from studies of healthy research participants suggests important contributions of the excitatory and inhibitory neurotransmitters glutamate and gamma-aminobutyric acid , respectively, to the resting state. In particular, glutamate and GABA appear to drive the metabolic and neuronal mechanisms underlying the resting state to sustain the excitation-inhibition balance . Indeed, resting-state metabolic activity of the brain is linearly coupled to its neuronal activity , largely reflecting the actions of glutamatergic and GABAergic neurons . Several combined fMRI-magnetic resonance spectroscopy studies have provided evidence supporting such relationships. For example, the higher the glutamate concentrations and the lower the GABA concentrations in the posterior cingulate cortex , the higher was the RSFC between PCC and pregenual anterior cingulate cortex . GABA concentrations, measured with MRS in the resting-state, were also negatively correlated with task-evoked fMRI activity in the pACC, visual cortex, and somatomotor cortex . The relationship between resting-state glutamate level and task-related activity is less clear , though it appears that glutamate mainly exerts transregional effects by acting on the long-range axons of pyramidal cells to enable cortico-cortical connections . In support of this view are observations that glutamate mediates the transition from resting-state activity in one region to stimulus-induced and restingstate activity in the same or different regions . The goals of the current article were: primarily to review evidence that human drug addiction is marked by abnormalities in brain glutamate and GABA; and secondarily to use findings of this literature in combination with select RSFC findings to build toward an initial plausible neurochemical framework underlying RSFC deficits in drug addiction, emphasizing important roles for glutamate and GABA.
In the primary section, we reviewed in vivo neurochemical imaging studies that tested for glutamatergic and GABAergic abnormalities in drug-addicted individuals as compared with healthy controls. The addictions considered were alcohol, nicotine/tobacco, opiates, cocaine, methamphetamine, and cannabis, each reviewed in turn. Imaging methods included magnetic resonance spectroscopy , which provides information on neurotransmitter or metabolite concentrations; and positron emission tomography and single proton emission computed tomography . PET and SPECT are nuclear medicine procedures that use tracer kinetic modeling to provide indices of neurotransmitter receptor binding, including: binding potential , the product of receptor density and affinity; volume of distribution , the ratio at equilibrium of the sum of the concentrations of specifically bound, non-specifically bound, and free radiotracer to that of parent radioligand in plasma, separated from radiometabolites; and distribution volume ratio , the volume of distribution normalized to nonspecific binding. Because abnormal activity of metabotropic glutamate receptors predisposes an individual to multiple disorders including addiction, the glutamate system has been assessed by PET with [11C]ABP688, a radioligand for the metabotropic glutamate receptor subtype 5 . In examining GABA neurotransmission, PET/SPECT studies have concentrated on the GABAA receptor, a Cl−ion channel that produces fast electrical signals and directly controls the efficacy of GABAergic synaptic transmission . These studies have primarily utilized three radiotracers: [11C]flumazenil and [123I]iomazenil, which bind to the benzodiazepine site on the GABAA receptor; and [11C]Ro15 4513, which binds to the GABAA receptor alpha-5 subunit . Signaling through GABAA receptors, particularly those containing an alpha-5 subunit, contributes to the reinforcing effects of alcohol in non-human animal studies . We stress from the outset that many interpretative difficulties emerge in reviewing this MRS and PET/SPECT literature, including multiple sources of variation between studies that can produce inconsistent findings. One notable difficulty is variation in participant characteristics. Participants often report the use of multiple drugs of abuse in varying amounts and at different times relative to testing, and their self-reports may contain inaccuracies; this difficulty is often accentuated in individuals addicted to illicit drugs, who regularly have more expansive drug use histories. For example, many drug abusers are also cigarette smokers, and smoking independently affects glutamate and other metabolites . Although most studies employ safeguards against effects of recent use , fine-grained information about participants’ secondary drug use histories are not routinely provided; understandably, most studies concentrate on the primary substance of abuse. Other sources of participant variation could include psychiatric comorbidities and their treatments. Methodologically, sources of variation include the use of small sample sizes in some imaging studies,vertical farming cost and differing and/or evolving sets of approaches and dependent variables. For example, MRS studies have measured glutamate signals in multiple ways [e.g., glutamate, glutamine, glutamate/glutamine, glutamine/ glutamate, and/or glutamate+glutamine ]. In keeping with the glutamate-glutamine cycle [i.e., the conversion of glutamate to glutamine in astrocytes is catalyzed by glutamine synthetase, and, in turn, glutamine is reconverted into glutamate in neurons by glutaminase ], ratios reflecting increased glutamate and/or decreased glutamine both putatively indicate increased brain glutamate levels.
Glutamate-related concentrations are sometimes further expressed as a ratio to creatine, often used as an internal reference metabolite . Given this heterogeneity of reporting, we attempted throughout to focus on effects from the perspective of glutamate or Glx. Such difficulties can also occur for GABA, although less so. Finally, it is possible that changes in the MRS glutamate/GABA resonance more immediately reflect changes in energy metabolism, and that changes in functional networks measurable by RSFC may stem more directly from such metabolic changes rather than from specific neurotransmission per se. This potential issue provides an important reason for including PET/SPECT studies that measured markers of glutamate and GABA neurotransmission. Taken together, even if these issues preclude full clarity regarding the directionality of effects at this time, our review of this literature serves to provide a macroscopic overview of the field and brings to light some inconsistencies that can be specifically addressed in future work. In the second section of this article, we reviewed select RSFC studies of addiction that followed from, and were informed by, the primary section . We did not intend for this section to exhaustive, nor did we describe each constituent study in complete depth and report every available analysis. Rather, we described representative RSFC findings in drug addiction, obtained using seed based and data-driven methodologies, which examined connectivity differences between addicted individuals and healthy controls in select corticolimbic brain regions [e.g., ACC, medial prefrontal cortex , striatum, and insula]. We marshaled this RSFC evidence, as well as evidence from the primary MRS/PET section, to support a new neurochemical framework in which we hypothesize that glutamatergic and/or GABAergic deficits may underlie RSFC abnormalities in drug addiction. RSFC, then, may serve as an intermediate phenotype bridging neurochemical abnormalities and addiction-relevant behaviors . We anticipate that this perspective can spearhead future hypothesis-driven research on this topic. In addition, an understanding of the neurochemical bases of the resting-state in drug addiction can also help advance the development of new therapeutics that target the relevant neurotransmitters and/or RSFC deficits.Individuals who abused addictive substances spanning alcohol, nicotine/tobacco, opiates, methamphetamine, and cannabis showed lower brain glutamate concentrations and/or mGluR5 receptor availability than corresponding measurements in controls. Differences most consistently emerged in multiple subregions of the ACC and in basal ganglia regions . A few exceptions to the general pattern of lower glutamate in addiction deserve mention: studies of cocaine users yielded some equivocal findings, although the findings were generally more consistent with the hypothesis of lower glutamate levels than higher glutamate levels; more research is needed on cannabis, especially while incorporating PET, before firm conclusions can be drawn; and when examining the use of multiple substances, MRS and PET studies yielded results that differed in direction, although each modality only had one relevant study and included different substances . Although with multiple exceptions, markers of reduced glutamatergic neurotrans mission were often correlated with greater drug-related impairment . A notable exception to this pattern was seen in some studies that showed positive correlation of glutamate levels with years of use. These findings suggest that the extent of dysregulation may vary with length of abuse . Interestingly, acute withdrawal instead tended to correlate with higher brain glutamate associated with the use of some substances . More work is needed to corroborate this withdrawal effect, however, as it was not consistently observed across all studies of early abstinent individuals even within the same substance . Nevertheless, this pattern of effects squares with findings showing that glutamate neurotransmission may be accentuated during acute withdrawal . Several studies reported increased radiotracer uptake in individuals with alcohol use disorder, but that these effects were blunted by active smoking. In particular, alcohol-addicted individuals in withdrawal had higher GABAA receptor availability, indexed by [123I]iomazenil VT, in the medial PFC, ACC, hippocampus-amygdala, and cerebellum, but these effects were less pronounced either if they were active smokers or after they achieved 4 weeks of alcohol abstinence . In the alcohol-addicted smokers, higher GABAA receptor availability was correlated with longer initial abstinence from alcohol . In a subsequent corroborative study, alcohol-addicted participants, further stratified by smoking status, were evaluated at 3, 10, and 30 days into withdrawal. Both alcohol-addicted smokers and non-smokers had higher GABAA receptor availability, indexed by [123I]iomazenil VT, compared with smoking-matched controls . However, smoking status modulated the neuroadaptations seen during withdrawal.