The theoretical framework of classical thermodynamics unifies vastly diverse natural phenomena and captures once-elusive effects in concrete terms. Neuroscience confronts equally varied, equally ineffable phenomena in the mental realm, but has yet to unite or to apprehend them rigorously, perhaps due to an insufficient theoretical framework. The terms for mental phenomena, the mental variables, typically used in neuroscience are overly numerous and imprecise. Unlike in thermodynamics or other branches of physics, in neuroscience, there are no core mental variables from which all others formally derive and it is unclear which variables are distinct and which overlap. This may be due to the nature of mental variables themselves. Unlike the variables of physics, perhaps they cannot be interpreted as composites of a small number of axioms. However, it is well worth exploring if they can, as that would allow more parsimonious theories of higher brain function. Here we offer a theoretical exercise in the spirit of the National Institutes of Health Research Domain Criteria (NIH RDoC) Initiative and the Cognitive Atlas Project, which aim to remedy this state of affairs. Imitating classical thermodynamics, we construct a formal framework for mental variables, an extended analogy - an allegory - between mental and thermodynamic quantities. Starting with mental correlates of the physical indefinables length, time, mass or force, and charge, we pursue the allegory up to mental versions of the thermodynamic Maxwell Relations. The Maxwell Relations interrelate the thermodynamic quantities volume, pressure, temperature, and entropy and were chosen since they are easy to derive, yet capable of generating nontrivial, nonobvious predictions. Our "Mental Maxwell Relations" interlink the mental variables consciousness, salience, arousal, and distraction and make nontrivial, nonobvious statements about mental phenomena. The mental system thus constructed is internally consistent, in harmony with introspection, and respects the RDoC criteria of employing only psychologically valid constructs with some evidence of a brain basis. We briefly apply these concepts to the problem of decision-making and sketch how some of them might be tested empirically.

This article reviews issues related to a major challenge to the field for obsessive-compulsive disorder (OCD): improving access to cognitive-behavioral therapy (CBT). Patient-related barriers to access include the stigma of OCD and reluctance to take on the demands of CBT. Patient-external factors include the shortage of trained CBT therapists and the high costs of CBT. The second half of the review focuses on one partial, yet plausible aid to improve access - prediction of long-term response to CBT, particularly using neuroimaging methods. Recent pilot data are presented revealing a potential for pretreatment resting-state functional magnetic resonance imaging and magnetic resonance spectroscopy of the brain to forecast OCD symptom severity up to 1 year after completing CBT.

Background

The acute phase of abstinence from methamphetamine abuse is critical for rehabilitation success. Proton magnetic resonance spectroscopy has detected below-normal levels of glutamate+glutamine in anterior middle cingulate of chronic methamphetamine abusers during early abstinence, attributed to abstinence-induced downregulation of the glutamatergic systems in the brain. This study further explored this phenomenon.

Methods

We measured glutamate+glutamine in additional cortical regions (midline posterior cingulate, midline precuneus, and bilateral inferior frontal cortex) putatively affected by methamphetamine. We examined the relationship between glutamate+glutamine in each region with duration of methamphetamine abuse as well as the depressive symptoms of early abstinence. Magnetic resonance spectroscopic imaging was acquired at 1.5 T from a methamphetamine group of 44 adults who had chronically abused methamphetamine and a control group of 23 age-, sex-, and tobacco smoking-matched healthy volunteers. Participants in the methamphetamine group were studied as inpatients during the first week of abstinence from the drug and were not receiving treatment.

Results

In the methamphetamine group, small but significant (5-15%, P<.05) decrements (vs control) in glutamate+glutamine were observed in posterior cingulate, precuneus, and right inferior frontal cortex; glutamate+glutamine in posterior cingulate was negatively correlated (P<.05) with years of methamphetamine abuse. The Beck Depression Inventory score was negatively correlated (P<.005) with glutamate+glutamine in right inferior frontal cortex.

Conclusions

Our findings support the idea that glutamatergic metabolism is downregulated in early abstinence in multiple cortical regions. The extent of downregulation may vary with length of abuse and may be associated with severity of depressive symptoms emergent in early recovery.

¹H magnetic resonance spectroscopy (MRS) can reveal changes in brain biochemistry in vivo in humans and has been applied to late onset Alzheimer disease (AD). Carriers of mutations for autosomal dominant Alzheimer disease (ADAD) may show changes in levels of metabolites prior to the onset of clinical symptoms. Proton MR spectra were acquired at 1.5 T for 16 cognitively asymptomatic or mildly symptomatic mutation carriers (CDR < 1) and 11 non-carriers as part of a comprehensive cross-sectional study of preclinical ADAD. Levels of N-acetyl-aspartate+N-acetyl-aspartyl-glutamate (NAA), glutamate/glutamine (Glx), creatine/phosphocreate (Cr), choline (Cho), and myo-inositol (mI) in the left and right anterior cingulate and midline posterior cingulate and precuneus were compared between mutation carriers (MCs) and non-carriers (NCs) using multivariate analysis of variance with age as a covariate. Among MCs, correlations between metabolite levels and time until expected age of dementia diagnosis were calculated. MCs had significantly lower levels of NAA and Glx in the left pregenual anterior cingulate cortex, and lower levels of NAA and higher levels of mI and Cho in the precuneus compared to NCs. Increased levels of mI were seen in these regions in association with increased proximity to expected age of dementia onset. MRS shows effects of ADAD similar to those seen in late onset AD even during the preclinical period including lower levels of NAA and higher levels of mI. These indices of neuronal and glial dysfunction might serve as surrogate outcome measures in prevention studies of putative disease-modifying agents.

Background

Despite rising prevalence of autism spectrum disorder (ASD), its brain bases remain uncertain. Abnormal levels of N-acetyl compounds, glutamate+glutamine, creatine+phosphocreatine, or choline compounds measured by proton magnetic resonance spectroscopy suggest that neuron or glial density, mitochondrial energetic metabolism, and/or inflammation contribute to ASD neuropathology. The neuroanatomic distribution of these metabolites could help evaluate leading theories of ASD. However, most prior magnetic resonance spectroscopy studies had small samples (all <60, most <20), interrogated only a small fraction of the brain, and avoided assessing effects of age, sex, and IQ.

Methods

We acquired near-whole-brain magnetic resonance spectroscopy of N-acetyl compounds, glutamate+glutamine, creatine+phosphocreatine, and choline compounds in 78 children and adults with ASD and 96 typically developing children and adults, rigorously evaluating effects of diagnosis and severity on metabolites, as moderated by age, sex, and IQ.

Results

Effects of ASD and its severity included reduced levels of multiple metabolites in white matter and the perisylvian cortex and elevated levels in the posterior cingulate, consistent with white matter and social-brain theories of ASD. Regionally, both slower and faster decreases of metabolites with age were observed in ASD versus TD. Male-female metabolite differences were widely smaller in ASD than typically developing children and adults. ASD-specific decreases in metabolites with decreasing IQ occurred in several brain areas.

Conclusions

Results support multifocal abnormal neuron or glial density, mitochondrial energetics, or neuroinflammation in ASD, alongside widespread starkly atypical moderating effects of age, sex, and IQ. These findings help parse the neurometabolic signature for ASD by phenotypic heterogeneity.

Cognitive behavioral therapy (CBT) is an effective treatment for many with obsessive-compulsive disorder (OCD). However, response varies considerably among individuals. Attaining a means to predict an individual's potential response would permit clinicians to more prudently allocate resources for this often stressful and time-consuming treatment. We collected resting-state functional magnetic resonance imaging from adults with OCD before and after 4 weeks of intensive daily CBT. We leveraged machine learning with cross-validation to assess the power of functional connectivity (FC) patterns to predict individual posttreatment OCD symptom severity. Pretreatment FC patterns within the default mode network and visual network significantly predicted posttreatment OCD severity, explaining up to 67% of the variance. These networks were stronger predictors than pretreatment clinical scores. Results have clinical implications for developing personalized medicine approaches to identifying individual OCD patients who will maximally benefit from intensive CBT.

Background

Methamphetamine induces neuronal N-acetyl-aspartate synthesis in preclinical studies. In a preliminary human proton magnetic resonance spectroscopic imaging investigation, we also observed that N-acetyl-aspartate+N-acetyl-aspartyl-glutamate in right inferior frontal cortex correlated with years of heavy methamphetamine abuse. In the same brain region, glutamate+glutamine is lower in methamphetamine users than in controls and is negatively correlated with depression. N-acetyl and glutamatergic neurochemistries therefore merit further investigation in methamphetamine abuse and the associated mood symptoms.

Methods

Magnetic resonance spectroscopic imaging was used to measure N-acetyl-aspartate+N-acetyl-aspartyl-glutamate and glutamate+glutamine in bilateral inferior frontal cortex and insula, a neighboring perisylvian region affected by methamphetamine, of 45 abstinent methamphetamine-dependent and 45 healthy control participants. Regional neurometabolite levels were tested for group differences and associations with duration of heavy methamphetamine use, depressive symptoms, and state anxiety.

Results

In right inferior frontal cortex, N-acetyl-aspartate+N-acetyl-aspartyl-glutamate correlated with years of heavy methamphetamine use (r = +0.45); glutamate+glutamine was lower in methamphetamine users than in controls (9.3%) and correlated negatively with depressive symptoms (r = -0.44). In left insula, N-acetyl-aspartate+N-acetyl-aspartyl-glutamate was 9.1% higher in methamphetamine users than controls. In right insula, glutamate+glutamine was 12.3% lower in methamphetamine users than controls and correlated negatively with depressive symptoms (r = -0.51) and state anxiety (r = -0.47).

Conclusions

The inferior frontal cortex and insula show methamphetamine-related abnormalities, consistent with prior observations of increased cortical N-acetyl-aspartate in methamphetamine-exposed animal models and associations between cortical glutamate and mood in human methamphetamine users.

Previous studies revealed microstructural abnormalities in prefrontal white matter and corpus callosum of long-term abstinent chronic methamphetamine abusers. In view of the importance of the early abstinence period in treatment retention, we compared 23 methamphetamine-dependent subjects abstinent from methamphetamine for 7–13 days with 18 healthy comparison subjects. As certain metabolic changes in the brain first manifest after early abstinence from methamphetamine, it is also possible that microstructural white-matter abnormalities are not yet present during early abstinence. Using diffusion tensor imaging at 1.5 T, fractional anisotropy (FA) was measured in prefrontal white matter at four inferior–superior levels parallel to the anterior commissure–posterior commissure (AC–PC) plane. We also sampled FA in the corpus callosum at the midline and at eight bilateral, fiber-tract sites in other regions implicated in effects of methamphetamine. The methamphetamine group exhibited lower FA in right prefrontal white matter above the AC–PC plane (11.9% lower; p = 0.007), in midline genu corpus callosum (3.9%; p = 0.019), in left and right midcaudal superior corona radiata (11.0% in both hemispheres, p’s = 0.020 and 0.016, respectively), and in right perforant fibers (7.3%; p = 0.025). FA in left midcaudal superior corona radiata was correlated with depressive and generalized psychiatric symptoms within the methamphetamine group. The findings support the idea that methamphetamine abuse produces microstructural abnormalities in white matter underlying and interconnecting prefrontal cortices and hippocampal formation. These effects are already present during the first weeks of abstinence from methamphetamine and are linked to psychiatric symptoms assessed during this period.

Prior research has identified OCD subtypes or "clusters" of symptoms that differentially relate to clinical features of the disorder. Given the high comorbidity between OCD and anxiety, OCD symptom clusters may more broadly associate with fear and/or distress internalizing constructs. This study examines fear and distress dimensions, including physical concerns (fear), separation anxiety (fear), perfectionism (distress), and anxious coping (distress), as predictors of previously empirically-derived OCD symptom clusters in a sample of 215 youth diagnosed with primary OCD (ages 7-17, mean age = 12.25). Self-reported separation fears predicted membership in Cluster 1 (aggressive, sexual, religious, somatic obsessions, and checking compulsions) while somatic/autonomic fears predicted membership in Cluster 2 (symmetry obsessions and ordering, counting, repeating compulsions). Results highlight the diversity of pediatric OCD symptoms and their differential association with fear, suggesting the need to carefully assess both OCD and global fear constructs that might be directly targeted in treatment.

The hemodynamic response function (HRF) represents the transfer function linking neural activity with the functional MRI (fMRI) signal, modeling neurovascular coupling. Since HRF is influenced by non-neural factors, to date it has largely been considered as a confound or has been ignored in many analyses. However, underlying biophysics suggests that the HRF may contain meaningful correlates of neural activity, which might be unavailable through conventional fMRI metrics. Here, we estimated the HRF by performing deconvolution on resting-state fMRI data from a longitudinal sample of 25 healthy controls scanned twice and 44 adults with obsessive-compulsive disorder (OCD) before and after 4-weeks of intensive cognitive-behavioral therapy (CBT). HRF response height, time-to-peak and full-width at half-maximum (FWHM) in OCD were abnormal before treatment and normalized after treatment in regions including the caudate. Pre-treatment HRF predicted treatment outcome (OCD symptom reduction) with 86.4% accuracy, using machine learning. Pre-treatment HRF response height in the caudate head and time-to-peak in the caudate tail were top-predictors of treatment response. Time-to-peak in the caudate tail, a region not typically identified in OCD studies using conventional fMRI activation or connectivity measures, may carry novel importance. Additionally, pre-treatment response height in caudate head predicted post-treatment OCD severity (R = -0.48, P = 0.001), and was associated with treatment-related OCD severity changes (R = -0.44, P = 0.0028), underscoring its relevance. With HRF being a reliable marker sensitive to brain function, OCD pathology, and intervention-related changes, these results could guide future studies towards novel discoveries not possible through conventional fMRI approaches like standard BOLD activation or connectivity.