Fetal testosterone influences sexually dimorphic gray matter in the human brain

In nonhuman species, testosterone is known to have permanent organizing effects early in life that predict later expression of sex differences in brain and behavior. However, in humans, it is still unknown whether such mechanisms have organizing effects on neural sexual dimorphism. In human males, we show that variation in fetal testosterone (FT) predicts later local gray matter volume of specific brain regions in a direction that is congruent with sexual dimorphism observed in a large independent sample of age-matched males and females from the NIH Pediatric MRI Data Repository. Right temporoparietal junction/posterior superior temporal sulcus (RTPJ/pSTS), planum temporale/parietal operculum (PT/PO), and posterior lateral orbitofrontal cortex (plOFC) had local gray matter volume that was both sexually dimorphic and predicted in a congruent direction by FT. That is, gray matter volume in RTPJ/pSTS was greater for males compared to females and was positively predicted by FT. Conversely, gray matter volume in PT/PO and plOFC was greater in females compared to males and was negatively predicted by FT. Subregions of both amygdala and hypothalamus were also sexually dimorphic in the direction of Male > Female, but were not predicted by FT. However, FT positively predicted gray matter volume of a non-sexually dimorphic subregion of the amygdala. These results bridge a long-standing gap between human and nonhuman species by showing that FT acts as an organizing mechanism for the development of regional sexual dimorphism in the human brain.

The primary somatosensory cortex largely contributes to the early part of the cortical response elicited by nociceptive stimuli.

Research on the cortical sources of nociceptive laser-evoked brain potentials (LEPs) began almost two decades ago (Tarkka and Treede, 1993). Whereas there is a large consensus on the sources of the late part of the LEP waveform (N2 and P2 waves), the relative contribution of the primary somatosensory cortex (S1) to the early part of the LEP waveform (N1 wave) is still debated. To address this issue we recorded LEPs elicited by the stimulation of four limbs in a large population (n=35). Early LEP generators were estimated both at single-subject and group level, using three different approaches: distributed source analysis, dipolar source modeling, and probabilistic independent component analysis (ICA). We show that the scalp distribution of the earliest LEP response to hand stimulation was maximal over the central-parietal electrodes contralateral to the stimulated side, while that of the earliest LEP response to foot stimulation was maximal over the central-parietal midline electrodes. Crucially, all three approaches indicated hand and foot S1 areas as generators of the earliest LEP response. Altogether, these findings indicate that the earliest part of the scalp response elicited by a selective nociceptive stimulus is largely explained by activity in the contralateral S1, with negligible contribution from the secondary somatosensory cortex (S2).

Causal evidence for frontal involvement in memory target maintenance by posterior brain areas during distracter interference of visual working memory

Dorsolateral prefrontal cortex (DLPFC) is recruited during visual working memory (WM) when relevant information must be maintained in the presence of distracting information. The mechanism by which DLPFC might ensure successful maintenance of the contents of WM is, however, unclear; it might enhance neural maintenance of memory targets or suppress processing of distracters. To adjudicate between these possibilities, we applied time-locked transcranial magnetic stimulation (TMS) during functional MRI, an approach that permits causal assessment of a stimulated brain region's influence on connected brain regions, and evaluated how this influence may change under different task conditions. Participants performed a visual WM task requiring retention of visual stimuli (faces or houses) across a delay during which visual distracters could be present or absent. When distracters were present, they were always from the opposite stimulus category, so that targets and distracters were represented in distinct posterior cortical areas. We then measured whether DLPFC-TMS, administered in the delay at the time point when distracters could appear, would modulate posterior regions representing memory targets or distracters. We found that DLPFC-TMS influenced posterior areas only when distracters were present and, critically, that this influence consisted of increased activity in regions representing the current memory targets. DLPFC-TMS did not affect regions representing current distracters. These results provide a new line of causal evidence for a top-down DLPFC-based control mechanism that promotes successful maintenance of relevant information in WM in the presence of distraction.

Lesions impairing regular versus irregular past tense production

We investigated selective impairments in the production of regular and irregular past tense by examining language performance and lesion sites in a sample of twelve stroke patients. A disadvantage in regular past tense production was observed in six patients when phonological complexity was greater for regular than irregular verbs, and in three patients when phonological complexity was closely matched across regularity. These deficits were not consistently related to grammatical difficulties or phonological errors but were consistently related to lesion site. All six patients with a regular past tense disadvantage had damage to the left ventral pars opercularis (in the inferior frontal cortex), an area associated with articulatory sequencing in prior functional imaging studies. In addition, those that maintained a disadvantage for regular verbs when phonological complexity was controlled had damage to the left ventral supramarginal gyrus (in the inferior parietal lobe), an area associated with phonological short-term memory. When these frontal and parietal regions were spared in patients who had damage to subcortical (n = 2) or posterior temporo-parietal regions (n = 3), past tense production was relatively unimpaired for both regular and irregular forms. The remaining (12th) patient was impaired in producing regular past tense but was significantly less accurate when producing irregular past tense. This patient had frontal, parietal, subcortical and posterior temporo-parietal damage, but was distinguished from the other patients by damage to the left anterior temporal cortex, an area associated with semantic processing. We consider how our lesion site and behavioral observations have implications for theoretical accounts of past tense production.

Causal evidence for a privileged working memory state in early visual cortex

Emerging evidence suggests that items held in working memory(WM)might not all be in the same representational state. One item might be privileged over others, making it more accessible and thereby recalled with greater precision. Here, using transcranial magnetic stimulation (TMS), we provide causal evidence in human participants that items inWMare differentially susceptible to disruptive TMS, depending on their state, determined either by task relevance or serial position. Across two experiments, we applied TMS to area MT during the WM retention of two motion directions. In Experiment 1, we used an “incidental cue” to bring one of the two targets into a privileged state. In Experiment 2, we presented the targets sequentially so that the last item was in a privileged state by virtue of recency. In both experiments, recall precision of motion direction was differentially affected by TMS, depending on the state of the memory target at the time of disruption. Privileged items were recalled with less precision, whereas nonprivileged items were recalled with higher precision. Thus, only the privileged item was susceptible to disruptive TMS over MT�. By contrast, precision of the nonprivileged item improved either directly because of facilitation by TMS or indirectly through reduced interference from the privileged item. Our results provide a unique line of evidence, as revealed by TMS over a posterior sensory brain region, for at least two different states of item representation in WM.

Visual processing of optic flow and motor control in the human posterior cingulate sulcus

Previous studies have shown that the human posterior cingulate contains a visual processing area selective for optic flow (CSv). However, other studies performed in both humans and monkeys have identified a somatotopic motor region at the same location (CMA). Taken together, these findings suggested the possibility that the posterior cingulate contains a single visuomotor integration region. To test this idea we used fMRI to identify both visual and motor areas of the posterior cingulate in the same brains and to test the activity of those regions during a visuomotor task. Results indicated that rather than a single visuomotor region the posterior cingulate contains adjacent but separate motor and visual regions. CSv lies in the fundus of the cingulate sulcus, while CMA lies in the dorsal bank of the sulcus, slightly superior in terms of stereotaxic coordinates. A surprising and novel finding was that activity in CSv was suppressed during the visuomotor task, despite the visual stimulus being identical to that used to localize the region. This may provide an important clue to the specific role played by this region in the utilization of optic flow to control self-motion.

Atypically rightward cerebral asymmetry in male adults with autism stratifies individuals with and without language delay

In humans, both language and fine motor skills are associated with left-hemisphere specialization, whereas visuospatial skills are associated with right-hemisphere specialization. Individuals with autism spectrum conditions (ASC) show a profile of deficits and strengths that involves these lateralized cognitive functions. Here we test the hypothesis that regions implicated in these functions are atypically rightward lateralized in individuals with ASC and, that such atypicality is associated with functional performance. Participants included 67 male, right-handed adults with ASC and 69 age- and IQ-matched neurotypical males. We assessed group differences in structural asymmetries in cortical regions of interest with voxel-based analysis of grey matter volumes, followed by correlational analyses with measures of language, motor and visuospatial skills. We found stronger rightward lateralization within the inferior parietal lobule and reduced leftward lateralization extending along the auditory cortex comprising the planum temporale, Heschl's gyrus, posterior supramarginal gyrus, and parietal operculum, which was more pronounced in ASC individuals with delayed language onset compared to those without. Planned correlational analyses showed that for individuals with ASC, reduced leftward asymmetry in the auditory region was associated with more childhood social reciprocity difficulties. We conclude that atypical cerebral structural asymmetry is a potential candidate neurophenotype of ASC

The effects of acute fluoxetine administration on temporal discounting in youth with ADHD

Background Serotonin is under-researched in attention deficit hyperactivity disorder (ADHD), despite accumulating evidence for its involvement in impulsiveness and the disorder. Serotonin further modulates temporal discounting (TD), which is typically abnormal in ADHD relative to healthy subjects, underpinned by reduced fronto-striato-limbic activation. This study tested whether a single acute dose of the selective serotonin reuptake inhibitor (SSRI) fluoxetine up-regulates and normalizes reduced fronto-striato-limbic neurofunctional activation in ADHD during TD. Method Twelve boys with ADHD were scanned twice in a placebo-controlled randomized design under either fluoxetine (between 8 and 15 mg, titrated to weight) or placebo while performing an individually adjusted functional magnetic resonance imaging TD task. Twenty healthy controls were scanned once. Brain activation was compared in patients under either drug condition and compared to controls to test for normalization effects. Results Repeated-measures whole-brain analysis in patients revealed significant up-regulation with fluoxetine in a large cluster comprising right inferior frontal cortex, insula, premotor cortex and basal ganglia, which further correlated trend-wise with TD performance, which was impaired relative to controls under placebo, but normalized under fluoxetine. Fluoxetine further down-regulated default mode areas of posterior cingulate and precuneus. Comparisons between controls and patients under either drug condition revealed normalization with fluoxetine in right premotor-insular-parietal activation, which was reduced in patients under placebo. Conclusions The findings show that a serotonin agonist up-regulates activation in typical ADHD dysfunctional areas in right inferior frontal cortex, insula and striatum as well as down-regulating default mode network regions in the context of impulsivity and TD.

Effects of Delta9-tetrahydrocannabivarin on [35S]GTPgammaS binding in mouse brain cerebellum and piriform cortex membranes

BACKGROUND AND PURPOSE: We have recently shown that the phytocannabinoid Delta9-tetrahydrocannabivarin (Delta9-THCV) and the CB1 receptor antagonist AM251 increase inhibitory neurotransmission in mouse cerebellum and also exhibit anticonvulsant activity in a rat piriform cortical (PC) model of epilepsy. Possible mechanisms underlying cannabinoid actions in the CNS include CB1 receptor antagonism (by displacing endocannabinergic tone) or inverse agonism at constitutively active CB1 receptors. Here, we investigate the mode of cannabinoid action in [35S]GTPgammaS binding assays. EXPERIMENTAL APPROACH: Effects of Delta9-THCV and AM251 were tested either alone or against WIN55,212-2-induced increases in [35S]GTPgammaS binding in mouse cerebellar and PC membranes. Effects on non-CB receptor expressing CHO-D2 cell membranes were also investigated. KEY RESULTS :Delta9-THCV and AM251 both acted as potent antagonists of WIN55,212-2-induced increases in [35S]GTPgammaS binding in cerebellar and PC membranes (Delta9-THCV: pA2=7.62 and 7.44 respectively; AM251: pA2=9.93 and 9.88 respectively). At micromolar concentrations, Delta9-THCV or AM251 alone caused significant decreases in [35S]GTPgammaS binding; Delta9-THCV caused larger decreases than AM251. When applied alone in CHO-D2 membranes, Delta9-THCV and AM251 also caused concentration-related decreases in G protein activity. CONCLUSIONS AND IMPLICATIONS: Delta9-THCV and AM251 act as CB1 receptors antagonists in the cerebellum and PC, with AM251 being more potent than Delta9-THCV in both brain regions. Individually, Delta9-THCV or AM251 exhibited similar potency at CB1 receptors in the cerebellum and the PC. At micromolar concentrations, Delta9-THCV and AM251 caused a non-CB receptor-mediated depression of basal [35S]GTPgammaS binding.

Sox1-deficient mice suffer from epilepsy associated with abnormal ventral forebrain development and olfactory cortex hyperexcitability

Mutations in several classes of embryonically-expressed transcription factor genes are associated with behavioral disorders and epilepsies. However, there is little known about how such genetic and neurodevelopmental defects lead to brain dysfunction. Here we present the characterization of an epilepsy syndrome caused by the absence of the transcription factor SOX1 in mice. In vivo electroencephalographic recordings from SOX1 mutants established a correlation between behavioral changes and cortical output that was consistent with a seizure origin in the limbic forebrain. In vitro intracellular recordings from three major forebrain regions, neocortex, hippocampus and olfactory (piriform) cortex (OC) showed that only the OC exhibits abnormal enhanced synaptic excitability and spontaneous epileptiform discharges. Furthermore, the hyperexcitability of the OC neurons was present in mutants prior to the onset of seizures but was completely absent from both the hippocampus and neocortex of the same animals. The local inhibitory GABAergic neurotransmission remained normal in the OC of SOX1-deficient brains, but there was a severe developmental deficit of OC postsynaptic target neurons, mainly GABAergic projection neurons within the olfactory tubercle and the nucleus accumbens shell. Our data show that SOX1 is essential for ventral telencephalic development and suggest that the neurodevelopmental defect disrupts local neuronal circuits leading to epilepsy in the SOX1-deficient mice

Cholinergic modulation of intrinsic fibre-evoked excitatory transmission contains a nicotinic component in immature but not adult rat piriform cortex, in vitro

The piriform cortex (PC) is highly prone to epileptogenesis, particularly in immature animals, where decreased muscarinic modulation of PC intrinsic fibre excitatory neurotransmission is implicated as a likely cause. However, whether higher levels of acetylcholine (ACh) release occur in immature vs. adult PC remains unclear. We investigated this using in vitro extracellular electrophysiological recording techniques. Intrinsic fibre-evoked extracellular field potentials (EFPs) were recorded from layers II to III in PC brain slices prepared from immature (P14-18) and adult (P>40) rats. Adult and immature PC EFPs were suppressed by eserine (1muM) or neostigmine (1muM) application, with a greater suppression in immature ( approximately 40%) than adult ( approximately 30%) slices. Subsequent application of atropine (1muM) reversed EFP suppression, producing supranormal ( approximately 12%) recovery in adult slices, suggesting that suppression was solely muscarinic ACh receptor-mediated and that some 'basal' cholinergic 'tone' was present. Conversely, atropine only partially reversed anticholinesterase effects in immature slices, suggesting the presence of additional non-muscarinic modulation. Accordingly, nicotine (50muM) caused immature field suppression ( approximately 30%) that was further enhanced by neostigmine, whereas it had no effect on adult EFPs. Unlike atropine, nicotinic antagonists, mecamylamine and methyllycaconitine, induced immature supranormal field recovery ( approximately 20%) following anticholinesterase-induced suppression (with no effect on adult slices), confirming that basal cholinergic 'tone' was also present. We suggest that nicotinic inhibitory cholinergic modulation occurs in the immature rat PC intrinsic excitatory fibre system, possibly to complement the existing, weak muscarinic modulation, and could be another important developmentally regulated system governing immature PC susceptibility towards epileptogenesis.

Developmental changes in presynaptic muscarinic modulation of excitatory and inhibitory neurotransmission in rat piriform cortex in vitro: relevance to epileptiform bursting susceptibility

Suppression of depolarizing postsynaptic potentials and isolated GABA-A receptor-mediated fast inhibitory postsynaptic potentials by the muscarinic acetylcholine receptor agonist, oxotremorine-M (10 microM), was investigated in adult and immature (P14-P30) rat piriform cortical (PC) slices using intracellular recording. Depolarizing postsynaptic potentials evoked by layers II-III stimulation underwent concentration-dependent inhibition in oxotremorine-M that was most likely presynaptic and M2 muscarinic acetylcholine receptor-mediated in immature, but M1-mediated in adult (P40-P80) slices; percentage inhibition was smaller in immature than in adult piriform cortex. In contrast, compared with adults, layer Ia-evoked depolarizing postsynaptic potentials in immature piriform cortex slices in oxotremorine-M, showed a prolonged multiphasic depolarization with superimposed fast transients and spikes, and an increased 'all-or-nothing' character. Isolated N-methyl-d-aspartate receptor-mediated layer Ia depolarizing postsynaptic potentials (although significantly larger in immature slices) were however, unaffected by oxotremorine-M, but blocked by dl-2-amino-5-phosphonovaleric acid. Fast inhibitory postsynaptic potentials evoked by layer Ib or layers II-III-fiber stimulation in immature slices were significantly smaller than in adults, despite similar estimated mean reversal potentials ( approximately -69 and -70 mV respectively). In oxotremorine-M, only layer Ib-fast inhibitory postsynaptic potentials were suppressed; suppression was again most likely presynaptic M2-mediated in immature slices, but M1-mediated in adults. The degree of fast inhibitory postsynaptic potential suppression was however, greater in immature than in adult piriform cortex. Our results demonstrate some important physiological and pharmacological differences between excitatory and inhibitory synaptic systems in adult and immature piriform cortex that could contribute toward the increased susceptibility of this region to muscarinic agonist-induced epileptiform activity in immature brain slices.

A novel component of cannabis extract potentiates excitatory synaptic transmission in rat olfactory cortex in vitro

Cannabis is a potential treatment for epilepsy, although the few human studies supporting this use have proved inconclusive. Previously, we showed that a standardized cannabis extract (SCE), isolated Delta(9)-tetrahydrocannabinol (Delta(9)-THC), and even Delta(9)-THC-free SCE inhibited muscarinic agonist-induced epileptiform bursting in rat olfactory cortical brain slices, acting via CB1 receptors. The present work demonstrates that although Delta(9)-THC (1microM) significantly depressed evoked depolarizing postsynaptic potentials (PSPs) in rat olfactory cortex neurones, both SCE and Delta(9)-THC-free SCE significantly potentiated evoked PSPs (all results were fully reversed by the CB1 receptor antagonist SR141716A, 1microM); interestingly, the potentiation by Delta(9)-THC-free SCE was greater than that produced by SCE. On comparing the effects of Delta(9)-THC-free SCE upon evoked PSPs and artificial PSPs (aPSPs; evoked electrotonically following brief intracellular current injection), PSPs were enhanced, whereas aPSPs were unaffected, suggesting that the effect was not due to changes in background input resistance. Similar recordings made using CB1 receptor-deficient knockout mice (CB1(-/-)) and wild-type littermate controls revealed cannabinoid or extract-induced changes in membrane resistance, cell excitability and synaptic transmission in wild-type mice that were similar to those seen in rat neurones, but no effect on these properties were seen in CB1(-/-) cells. It appears that the unknown extract constituent(s) effects over-rode the suppressive effects of Delta(9)-THC on excitatory neurotransmitter release, which may explain some patients' preference for herbal cannabis rather than isolated Delta(9)-THC (due to attenuation of some of the central Delta(9)-THC side effects) and possibly account for the rare incidence of seizures in some individuals taking cannabis recreationally

Inverse amygdala and medial prefrontal cortex responses to surprised faces

Here we show inverse fMRI activation patterns in amygdala and medial prefrontal cortex (mPFC) depending upon whether subjects interpreted surprised facial expressions positively or negatively. More negative interpretations of surprised faces were associated with greater signal changes in the right ventral amygdala, while more positive interpretations were associated with greater signal changes in the ventral mPFC. Accordingly, signal change within these two areas was inversely correlated. Thus, individual differences in the judgment of surprised faces are related to a systematic inverse relationship between amygdala and mPFC activity, a circuitry that the animal literature suggests is critical to the assessment of stimuli that predict potential positive vs negative outcomes.

Amygdala and ventromedial prefrontal cortex are inversely coupled during regulation of negative affect and predict the diurnal pattern of cortisol secretion among older adults

Among younger adults, the ability to willfully regulate negative affect, enabling effective responses to stressful experiences, engages regions of prefrontal cortex (PFC) and the amygdala. Because regions of PFC and the amygdala are known to influence the hypothalamic-pituitary-adrenal axis, here we test whether PFC and amygdala responses during emotion regulation predict the diurnal pattern of salivary cortisol secretion. We also test whether PFC and amygdala regions are engaged during emotion regulation in older (62- to 64-year-old) rather than younger individuals. We measured brain activity using functional magnetic resonance imaging as participants regulated (increased or decreased) their affective responses or attended to negative picture stimuli. We also collected saliva samples for 1 week at home for cortisol assay. Consistent with previous work in younger samples, increasing negative affect resulted in ventral lateral, dorsolateral, and dorsomedial regions of PFC and amygdala activation. In contrast to previous work, decreasing negative affect did not produce the predicted robust pattern of higher PFC and lower amygdala activation. Individuals demonstrating the predicted effect (decrease s attend in the amygdala), however, exhibited higher signal in ventromedial prefrontal cortex (VMPFC) for the same contrast. Furthermore, participants displaying higher VMPFC and lower amygdala signal when decreasing compared with the attention control condition evidenced steeper, more normative declines in cortisol over the course of the day. Individual differences yielded the predicted link between brain function while reducing negative affect in the laboratory and diurnal regulation of endocrine activity in the home environment.